Estrogen receptor modulators

ABSTRACT

Described herein, inter alia, are compositions and methods for treating or preventing hyperproliferative disorders, including cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/084,884, filed Nov. 26, 2014, the contents of which is herebyincorporated herein in its entirety and for all purposes.

BACKGROUND OF THE INVENTION

Breast cancer is the most common malignancy in women in North America.Each year more than 210,000 new cases of breast cancer are diagnosed inthe US (1-3). In the clinic, endocrine therapy is an importantintervention for cancers that express estrogen receptor (ER), and it hasproven to be one of the most effective treatment strategies for breastcancer (3,4). At diagnosis, about 70% of breast cancers contain estrogenreceptors and depend on estrogen for growth and progression. Expressionof ER in a tumor is predictive of a clinical response to hormonaltherapy. Such observations have led to current use of antiestrogens(such as fulvestrant, tamoxifen and its relatives, raloxifene,toremifene, lasofoxifene, etc.) and aromatase inhibitors in treatingER-positive breast cancer (2,3). Tamoxifen and its analogues are amongthe most highly prescribed drugs for initial estrogen-dependent breastcancer. However, they are not without their drawbacks since they bind tothe estrogen receptor in many tissues (bone, uterus, etc.) and can haveharmful effects. A substantial proportion of patients presenting withlocalized disease, and all of the patients with metastatic breastcancer, become resistant to current endocrine therapies (5, 6). Thus,there is an urgent need to develop alternative therapeutics to overcomeendocrine resistance and to improve the long-term survival of afflictedpatients. Despite remarkable improvements in treatment options,development of endocrine resistance is one reason that breast cancer isthe second most frequent cause of cancer death in women (5-7). In mostcases, the ER is present in resistant tumors, and in many of these itsactivity continues to regulate tumor growth.

Classical and nonclassical mechanisms of estrogen action in breastmalignancy. Estrogen modulates gene transcription in breast cancersthrough its receptors using different signaling pathways (2,8) (see FIG.1). The classical pathway involves direct DNA binding of ligandedreceptor to estrogen response elements (EREs) in the promoter regions ofresponsive genes.

The proliferation and survival of breast cancers is closely regulated bygrowth factor receptors as well as estrogens (E2) and their receptors,estrogen receptor (ER)-α and -β, with ERα generally considered mostimportant in tumor progression (5,6,9). ERα has 6 major functionaldomains including an N-terminal transactivation domain, an adjacentDNA-binding domain and a C-terminal portion involved in hormone-binding,receptor dimerization and activity of a second transactivation region.In classical models of E2 action, E2 binds ER to promote dimerizationand phosphorylation of the receptor. This allows direct binding of theligand-ER complex with steroid receptor coactivators (CoReg) andE2-responsive elements (ERE) in DNA, leading to changes in genetranscription that regulate growth, differentiation, apoptosis andangiogenesis. In addition, there are alternate pathways of E2 actionthat involve protein-protein interactions and do not require direct ERbinding to DNA. A subset of ER associate with extranuclear sites andinteract there with membrane growth factor receptors (EGFR, HER2) andother signaling molecules (components of the ras-MAPK and PI3K/AKTpathways, Shc, src kinases, JAK/STAT, nitric oxide synthase (NOS),G-proteins). Of special note, growth factor and extranuclear estrogenreceptors appear to form a structured complex for signal transduction toMAPK and/or PI3K/AKT kinase that interacts, in turn, with nuclear ER andCoReg. Signaling for cell growth involves phosphorylation (P) of nuclearER and CoReg, and such phosphorylation can occur in ligand-dependent aswell as ligand-independent modes. ERE-dependent and alternatetranscription sites may be activated. Further, E2 is produced locally insupporting cells by the action of aromatase (ARO), and ARO is regulatedby both nulcear and extranuclear ER and growth factor-mediatedsignaling. In addition, estrogens may regulate tumor-associatedangiogenesis by direct interactions with vascular endothelial cells orby indirect stimulation of VEGF secretion from tumors.

However, it is now clear that the ERα can regulate genes that lack acanonical ERE, suggesting additional pathways for estrogen action thatmay be of paramount importance in modulating tumor progression.Alternate, nonclassical pathways involve indirect modulation oftranscription by ER interaction with components of other transcriptioncomplexes (AP-1, nuclear factor-kB) or kinase signaling complexes (MAPK,PI3K/AKT kinase) via protein-protein interactions. Emerging data suggestthat interactions of ER with growth factor receptor-kinase signalingpathways may play a critical role in promoting estrogen signaling fortumor progression (9). Based on current data in estrogen target cells,nonclassical ER signaling is associated with epithelial proliferationbut not other estrogen-responsive events such as fluid accumulation inuterus (8), while classical ER signaling appears more essential forskeletal development, bone health and other differentiated cellfunctions (10).

ER often continues to play a major role in controlling growth ofhormone-resistant cancers. In treatment with aromatase inhibitors(AI's), ER activation by alternate ligands, local E2 production anddevelopment of ER hypersensitivity are especially problemsome (2,6). Inaddition, ligand-independent activation of ER occurs in tumorsoverexpressing growth factor receptors such as HER2, with growth factorreceptors promoting ER phosphorylation even in the absence of estrogen(5,9,11). Such ligand-independent mechanisms likely contribute toresistance to AI's as well as antiestrogens (12,13). These nonclassicalevents are mediated by ER or adaptor proteins that impact geneexpression indirectly by activating growth-promoting kinase cascades toregulate transcription. In breast tumors, significant evidence suggeststhat regulation of both proliferation and cell death pathways occurs, inpart, by the action of nonclassical kinase-mediated pathways(9,11,14-19). Better understanding and targeting of these complexsignaling pathways in tumors with endocrine resistance to bothantiestrogens and AI's will help in development of individualized andimproved treatments in the clinic.

Current antiestrogens are competitive antagonists of estrogen anddisrupt ER-induced transcription. However, some antagonists displaypartial estrogenic activity in a tissue- and gene-dependent manner,hence their description as selective estrogen receptor modulators(SERMs). Tamoxifen, a partial agonist that limits effects of E2 inbreast, has been the most widely used hormone therapy for the past 20years, achieving a 39% reduction in disease recurrence and a 31%reduction in mortality in ER+ early breast cancer (6,20,21). Althougheffective, tamoxifen has an important drawback—the limited period ofactivity before resistance develops (7,20). Further, prolonged treatmentwith tamoxifen is associated with an increased risk for endometrialcancer due to significant agonist activity of the drug in uterus. Aslong as the ER is present in tumors, growth may still be stimulated bysmall amounts of estrogens or antiestrogens or by ligand-independentactions. The introduction of AI's for postmenopausal patients, eitherinitially, or sequentially after tamoxifen, may produce better outcomesthan the standard treatment of 5 years of tamoxifen (22-24).Nonetheless, in patients with advanced disease, only about ⅓ of HR+tumors respond to AI's as first-line treatments (6). Further, resistanceto AI's also develops due, in part, to E2-independent mechanisms(6,12,13). Consequently, a search has begun to find new antiestrogensthat do not display agonist activity or lead to development ofresistance. The first prototype drug, fulvestrant (25), is a pure ERantagonist that also exhibits a unique mechanism ofaction—downregulation of ER due in part to induced hyperubiquitinationof ER (26,27). As fulvestrant has no agonistic activity but insteaddestabilizes ER, the drug elicits marked disruption of ER-mediatedgrowth. However, fulvestrant has a major drawback—very lowbioavailability—which is problemsome in the clinic. Although fulvestranthas activity in treating ER+ metastatic breast cancer in postmenopausalwomen with disease progression after tamoxifen or AI therapy (7,28,29),discovery of new ER antagonists with improved bioavailability andantitumor activity remains an important goal.

ER degradation limits hormone action. Ligand-induced down-regulation ofER is a pivotal step in halting E2 stimulation of growth, and theubiquitin-proteasome pathway is the major system for selectivedegradation of such regulatory proteins (30). ERα was among the first ofthe nuclear receptors identified as substrates for this pathway (31-34).A common feature of proteasome-mediated protein degradation is covalentattachment of ubiquitin to lysine residues of proteins targeted fordegradation followed by formation of polyubiquitin chains attachedcovalently to the protein. Ubiquitinated ERα is recognized and degradedby the multisubunit protease complex, the 26S proteasome (35). ER isdegraded in a hormone-dependent manner, with this process contributingto regulation of hormone action; and the proteasome inhibitor, MG132, iswell known to promote in vivo accumulation of ER and to blockligand-induced ER degradation (33). As noted above, the proteasomepathway also plays a critical role in interaction of ER withantagonists, such as SERMs and fulvestrant (27,34).

Therefore it would be useful to test new novel ER antagonists to findcompounds which inhibit the growth of hyperproliferative cells,including breast cancer. Disclosed herein, inter alia, are solutions tothese and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

In an aspect is provided a compound, or a pharmaceutically acceptablesalt thereof, having the formula:

R¹ is independently a hydrogen,

halogen, —NR²R³, —CX^(a) ₃, —CN, —SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR²R³,—NHNR²R³, —ONR²R³, —NHC═(O)NHNR²R³, —NHC═(O)NR²R³, —N(O)_(m1), —C(O)R⁹,—C(O)—OR⁹, —C(O)NR²R³, —OR¹⁰, —NR²SO₂R¹⁰, —NR²C═(O)R⁹, —NR²C(O)—OR⁹,—NR²OR⁹, —OCX^(a) ₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R² is independently a hydrogen,

halogen, —CX^(b) ₃, —CN, —SO₂Cl, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂,—ONR¹¹R¹², —NHC═(O)NHNH₂, —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX^(b) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R³ is independently a hydrogen, halogen, —CX^(c) ₃, —CN,—SO₂Cl, —SO_(n3)R¹⁸, —SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁵SR¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷,—C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷,—NR¹⁵OR⁷, —OCX^(c) ₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R² andR³ substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

L is independently a bond, —NR⁴—, —NR⁴C(O)—, —C(O)NR⁴—, —O—, —S—,—C(O)—, —S(O)—, —S(O)₂—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene; or a substituted or unsubstitutedspirocyclic linker. R⁴ is independently a hydrogen, halogen, —CX^(d) ₃,—CN, —SO₂Cl, —SO_(n4)R²², —SO_(v4)NR¹⁹R²⁰, —NHNH₂, —ONR¹⁹R²⁰,—NHC═(O)NHNH₂,

—NHC═(O)NR¹⁹R²⁰, —N(O)_(m4), —NR¹⁹R²⁰, —C(O)R²¹, —C(O)—OR²¹,—C(O)NR¹⁹R²⁰, —OR²², —NR¹⁹SO₂R²², —NR¹⁹C═(O)R²¹, —NR¹⁹C(O)—OR²¹,—NR¹⁹OR²¹, —OCX^(d) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²²are independently hydrogen, halogen, —CX₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹and R¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹⁵ and R¹⁶ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R¹⁹ and R²⁰ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

The symbol n is an integer from 0 to 5. The symbols m1, m2, m3, m4, v1,v2, v3, and v4 are independently 1 or 2. The symbols n1, n2, n3, and n4are independently an integer from 0 to 4. The symbols X, X^(a), X^(b),X^(c) and X^(d) are independently —Cl, —Br, —I, or —F.

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, as described herein, includingembodiments (e.g. compound of formula I, Ia, Ib, II, IIa, IIb, or anyembodiment thereof, or in an example, table, figure, or claim).

In an aspect is provided a method of treating a hyperproliferativedisorder in a subject in need thereof, including administering to thesubject an effective amount of a compound described herein.

In an aspect is provided a method of inhibiting estrogen receptoractivity in a subject in need thereof, including administering to thesubject an effective amount of a compound described herein.

In an aspect is provided a method of treating a bone disorder in asubject in need thereof, including administering to the subject aneffective amount of a compound described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Interactions of estrogen and growth factor receptor signalingpathways in cancer cells.

FIG. 2. Inhibition of estrogen receptor-positive human breast cancercell proliferation by novel antiestrogens.

FIG. 3. Estrogen receptor-alpha is down-regulated by antiestrogens.

FIGS. 4A-4B. MCF-7 cells with acquired tamoxifen resistance showincreased expression of HER-1/EGFR and HER-2 receptors.

FIG. 5. Specific binding of [3H]estradiol-17β by MCF-7 parental breastcancer cells is suppressed by ERD compound 15 (JD105). Compounds S1-S14in the present figure are comparative test compounds (different fromindividual compounds described herein) showing less inhibition thancompound S15 in the present assay.

FIG. 6. ERD S15 reduces ER protein levels in MCF-7 breast tumor cells.

FIG. 7. Treatment of MCF-7 parent cells with 1 nM estradiol 17β (E2)induces rapid phosphorylation of MAPK (pMAPK).

FIG. 8. Novel antiestrogen JD140 elicits significant antiproliferativeeffects in human non-small cell lung cancer cells A549 as compared withthe activity of fulvestrant.

FIG. 9. Activation of estrogen receptor (ER) by estradiol-17β or bygrowth factor receptor signaling promotes gene transcription for tumorcell proliferation and inhibition of apoptosis. Disruption by selectiveestrogen receptor downregulators of critical steps in these pathwaysincludes downstream actions such as modulation of cyclin D expression inthe control of the cell cycle and proliferation and regulation ofapoptosis.

DETAILED DESCRIPTION OF THE INVENTION

A primary goal of this work is to design, synthesize, test and furtherdevelop small organic SERMs that elicit ERdestabilization/downregulation and inhibit tumor cell growth. Thisaction-suppression of ER protein expression- is critical to stopligand-dependent and ligand-independent modes of hormone resistance.Described herein are unique, selective ER antagonists that targetgrowth-promoting signaling pathways induced by ER and that exhibit theproper biologic and pharmacologic profile to be ultimately developed astherapeutics for endocrine-sensitive and -resistant cancers in theclinic.

Described herein is the design and synthesis of several novel analoguesof estradiol having sterically large and positively charged groups onthe β-face of the molecule. These compounds may bind to the ER and causehelix 12 to not fold properly and therefore that would interrupt thetransmission of the signal for cancer growth. Biological testing hasshown that many of the analogues have excellent growth inhibitoryactivity, at least as good or better than the commercial drug,Faslodex®. Compounds described herein have great promise as agentsagainst hyperproliferative disorders (e.g., breast cancer).

A. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O—is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchednon-cyclic carbon chain (or carbon), or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—). An alkyl moietymay be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. Analkyl moiety may be fully saturated.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable non-cyclic straight or branchedchain, or combinations thereof, including at least one carbon atom andat least one heteroatom (e.g. O, N, P, Si, and S) and wherein thenitrogen and sulfur atoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) (e.g. O, N,P, S, and Si) may be placed at any interior position of the heteroalkylgroup or at the position at which the alkyl group is attached to theremainder of the molecule. Examples include, but are not limited to:—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, —C—H═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up totwo or three heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include oneheteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includetwo optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include three optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include fouroptionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,3-hydroxy-cyclobut-3-enyl-1,2, dione, 1H-1,2,4-triazolyl-5(4H)-one,4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include,but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means a divalent radical derived from a cycloalkyl andheterocycloalkyl, respectively. A heterocycloalkyl moiety may includeone ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moietymay include two optionally different ring heteroatoms (e.g., O, N, S,Si, or P). A heterocycloalkyl moiety may include three optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include four optionally different ring heteroatoms (e.g., O,N, S, Si, or P). A heterocycloalkyl moiety may include five optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include up to 8 optionally different ring heteroatoms (e.g.,O, N, S, Si, or P).

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. Non-limiting examples of aryl and heteroarylgroups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl,indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl,pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl,quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl,benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl,pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl,furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl,benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl,diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl,or quinolyl. The examples above may be substituted or unsubstituted anddivalent radicals of each heteroaryl example above are non-limitingexamples of heteroarylene. A heteroaryl moiety may include one ringheteroatom (e.g., O, N, or S). A heteroaryl moiety may include twooptionally different ring heteroatoms (e.g., O, N, or S). A heteroarylmoiety may include three optionally different ring heteroatoms (e.g., O,N, or S). A heteroaryl moiety may include four optionally different ringheteroatoms (e.g., O, N, or S). A heteroaryl moiety may include fiveoptionally different ring heteroatoms (e.g., O, N, or S). An aryl moietymay have a single ring. An aryl moiety may have two optionally differentrings. An aryl moiety may have three optionally different rings. An arylmoiety may have four optionally different rings. A heteroaryl moiety mayhave one ring. A heteroaryl moiety may have two optionally differentrings. A heteroaryl moiety may have three optionally different rings. Aheteroaryl moiety may have four optionally different rings. A heteroarylmoiety may have five optionally different rings.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl”,“heterocycloalkyl”, “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, in a number ranging from zeroto (2m′+1), where m′ is the total number of carbon atoms in suchradical. R, R′, R″, R′″, and R″″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted heteroaryl, substituted orunsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.When a compound of the invention includes more than one R group, forexample, each of the R groups is independently selected as are each R′,R″, R′″, and R″″ group when more than one of these groups is present.When R′ and R″ are attached to the same nitrogen atom, they can becombined with the nitrogen atom to form a 4-, 5-, 6-, or 7-memberedring. For example, —NR′R″ includes, but is not limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for

example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃,—CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R″, R′″, and R″″ are preferably independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ groups when more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted        heteroalkyl, unsubstituted cycloalkyl, unsubstituted        heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl,        and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,            —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,            —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted            heteroalkyl, unsubstituted cycloalkyl, unsubstituted            heterocycloalkyl, unsubstituted aryl, unsubstituted            heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo,            -   halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,                —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present invention containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present invention. Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Provided herein are agents (e.g. compounds, drugs, therapeutic agents)that may be in a prodrug form. Prodrugs of the compounds describedherein are those compounds that readily undergo chemical changes underselect physiological conditions to provide the final agents (e.g.compounds, drugs, therapeutic agents). Additionally, prodrugs can beconverted to agents (e.g. compounds, drugs, therapeutic agents) bychemical or biochemical methods in an ex vivo environment. Prodrugsdescribed herein include compounds that readily undergo chemical changesunder select physiological conditions to provide agents (e.g. compounds,drugs, therapeutic agents) to a biological system (e.g. in a subject, ina cancer cell, in the extracellular space near a cancer cell).

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “,” denotes the point of attachment of a chemical moiety tothe remainder of a molecule or chemical formula.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,certain methods herein treat diseases associated with estrogen receptoractivity. Certain methods described herein may treat diseases associatedwith estrogen receptor activity (e.g., breast cancer, lung cancer, agynecological cancer, ovarian cancer, endometrial cancer, or prostatecancer, lymphangioleiomyomatosis (LAM)) by inhibiting estrogen receptoractivity. Certain methods described herein may treat diseases associatedwith estrogen receptor activity by inhibiting ligand binding to estrogenreceptor. Certain methods described herein may treat diseases associatedwith estrogen receptor activity by inducing the degradation of estrogenreceptor. Certain methods described herein may treat diseases associatedwith estrogen receptor activity by inducing a non-active conformation ofestrogen receptor. Certain methods described herein may treat diseasesassociated with hyperproliferation (e.g., of cells). For example,certain methods herein treat cancer. For example certain methods hereintreat cancer by decreasing a symptom of cancer. Symptoms of cancer wouldbe known or may be determined by a person of ordinary skill in the art.The term “treating” and conjugations thereof, include prevention ofinjury, pathology, condition, or disease.

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reduceprotein function, reduce one or more symptoms of a disease orcondition). An example of an “effective amount” is an amount sufficientto contribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug or prodrugis an amount of a drug or prodrug that, when administered to a subject,will have the intended prophylactic effect, e.g., preventing or delayingthe onset (or reoccurrence) of an injury, disease, pathology orcondition, or reducing the likelihood of the onset (or reoccurrence) ofan injury, disease, pathology, or condition, or their symptoms. The fullprophylactic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a prophylactically effective amount may be administered in one ormore administrations. The exact amounts will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g.hyperproliferative disease, cancer) means that the disease is caused by(in whole or in part), or a symptom of the disease is caused by (inwhole or in part) the substance or substance activity or function. Asused herein, what is described as being associated with a disease, if acausative agent, could be a target for treatment of the disease. Forexample, a disease associated with estrogen receptor activity may betreated with an agent (e.g. compound as described herein) effective fordecreasing the level of estrogen receptor activity.

“Control” or “control experiment” or “standard control” is used inaccordance with its plain ordinary meaning and refers to an experimentin which the subjects or reagents of the experiment are treated as in aparallel experiment except for omission of a procedure, reagent, orvariable of the experiment. In some instances, the control is used as astandard of comparison in evaluating experimental effects.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, that the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme. In some embodiments contacting includes allowing a compounddescribed herein to interact with a protein or enzyme.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor (e.g. antagonist)interaction means negatively affecting (e.g. decreasing) the level ofactivity or function of the protein relative to the level of activity orfunction of the protein in the absence of the inhibitor. In someembodiments inhibition refers to reduction of a disease or symptoms ofdisease. Thus, inhibition may include, at least in part, partially ortotally blocking stimulation, decreasing, preventing, or delayingactivation, or inactivating, desensitizing, or down-regulating signaltransduction or enzymatic activity or the amount of a protein.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator (e.g. agonist) interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein relative to the activity or function of the protein in theabsence of the activator (e.g. compound described herein). Thus,activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.Activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule. Inembodiments, a modulator is an anti-cancer agent. In embodiments, amodulator is an estrogen receptor antagonist. In embodiments, amodulator is a hormone receptor antagonist. In embodiments, a modulatoris an estrogen receptor inhibitor. In embodiments, a modulator is anestrogen receptor covalent modifier.

“Anti-cancer agent” or “anti-cancer drug” is used in accordance with itsplain ordinary meaning and refers to a composition (e.g. compound, drug,antagonist, inhibitor, modulator) having antineoplastic properties orthe ability to inhibit the growth or proliferation of cells. In someembodiments, an anti-cancer agent is a chemotherapeutic. In someembodiments, an anti-cancer agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcancer. Examples of anti-cancer agents include, but are not limited to,anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK(e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040,PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973,ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733,PD318088, AS703026, BAY 869766), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomusitne, semustine, streptozocin), triazenes (decarbazine),anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine,fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog(e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel,docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.),antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin,epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin,etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin,carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea(e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide),epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin,doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors ofmitogen-activated protein kinase signaling (e.g. U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan),5-aza-2′-deoxycytidine, doxorubicin, vincristine, etoposide,gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), bortezomib,trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogen,antiestrogen; antisense oligonucleotides; apoptosis gene modulators;apoptosis regulators; arginine deaminase; BCR/ABL antagonists; betalactam derivatives; bFGF inhibitor; bicalutamide; camptothecinderivatives; casein kinase inhibitors (ICOS); clomifene analogues;cytarabine dacliximab; dexamethasone; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;finasteride; fludarabine; fluorodaunorunicin hydrochloride; gadoliniumtexaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; letrozole; leukemia inhibiting factor;leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; mismatched double stranded RNA; monoclonalantibody; mycobacterial cell wall extract; nitric oxide modulators;oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogenactivator inhibitor; platinum complex; platinum compounds; prednisone;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; ribozymes; signal transductioninhibitors; signal transduction modulators; single chain antigen-bindingprotein; stem cell inhibitor; stem-cell division inhibitors; stromelysininhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;telomerase inhibitors; thyroid stimulating hormone; translationinhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists;steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,gonadotropin-releasing hormone agonists (GnRH) such as goserelin orleuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, pyrrolo benzodiazepines (e.g. tomaymycin),carboplatin, CC-1065 and CC-1065 analogs including amino-CBIs, nitrogenmustards (such as chlorambucil and melphalan), dolastatin and dolastatinanalogs (including auristatins: eg. monomethyl auristatin E),anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.),duocarmycins and duocarmycin analogs, enediynes (such asneocarzinostatin and calicheamicins), leptomycin derivaties,maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate,mitomycin C, taxoids, vinca alkaloids (such as vinblastine andvincristine), epothilones (e.g. epothilone B), fluvestrant, camptothecinand its clinical analogs topotecan and irinotecan, SERMS (e.g.,clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene,lasofoxifene, ospemifene), aromatase inhibitors (e.g., anastrozole,letrozole, exemestane, vorozole, formestane, fadrozole,aminoglutethimide, testolactone), or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

“Patient” or “subject in need thereof” or “subject” refers to a livingorganism suffering from or prone to a disease or condition that can betreated by administration of a compound or pharmaceutical composition orby a method, as provided herein. Non-limiting examples include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In some embodiments, a patient ishuman. In some embodiments, a subject is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is a disease having the symptom of cellhyperproliferation. In some embodiments, the disease is a disease havingthe symptom of an aberrant level of estrogen receptor activity. In someembodiments, the disease is a cancer. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma. In embodiments, the disease is breast cancer. Inembodiments, the disease is hormone sensitive breast cancer. Inembodiments, the disease is hormone refractory (insensitive) breastcancer. In embodiments, the disease is ER positive breast cancer. Inembodiments, the disease is ER negative breast cancer. In embodiments,the disease is breast cancer expressing HER-2.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound or method provided herein include cancer of theprostate, thyroid, endocrine system, brain, breast, cervix, colon, head& neck, liver, kidney, lung, non-small cell lung, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma,colorectal cancer, pancreatic cancer. Additional examples may include,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity, aberrant refers to activity that isgreater or less than a normal control or the average of normalnon-diseased control samples. Aberrant activity may refer to an amountof activity that results in a disease, wherein returning the aberrantactivity to a normal or non-disease-associated amount (e.g. byadministering a compound or using a method as described herein), resultsin reduction of the disease or one or more disease symptoms.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammaticalequivalents used herein means at least two nucleotides covalently linkedtogether. The term “nucleic acid” includes single-, double-, ormultiple-stranded DNA, RNA and analogs (derivatives) thereof.Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25,30, 40, 50 or more nucleotides in length, up to about 100 nucleotides inlength. Nucleic acids and polynucleotides are a polymers of any length,including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000,7000, 10,000, etc. Nucleic acids containing one or more carbocyclicsugars are also included within one definition of nucleic acids.

A particular nucleic acid sequence also encompasses “splice variants.”Similarly, a particular protein encoded by a nucleic acid encompassesany protein encoded by a splice variant of that nucleic acid. “Splicevariants,” as the name suggests, are products of alternative splicing ofa gene. After transcription, an initial nucleic acid transcript may bespliced such that different (alternate) nucleic acid splice productsencode different polypeptides. Mechanisms for the production of splicevariants vary, but include alternate splicing of exons. Alternatepolypeptides derived from the same nucleic acid by read-throughtranscription are also encompassed by this definition. Any products of asplicing reaction, including recombinant forms of the splice products,are included in this definition.

A nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are near each other, and, inthe case of a secretory leader, contiguous and in reading phase.However, enhancers do not have to be contiguous. Linking is accomplishedby ligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same or have a specifiedpercentage of amino acid residues or nucleotides that are the same(i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or higher identity over a specified region whencompared and aligned for maximum correspondence over a comparison windowor designated region) as measured using a BLAST or BLAST 2.0 sequencecomparison algorithms with default parameters described below, or bymanual alignment and visual inspection (see, e.g., NCBI web site or thelike). Such sequences are then said to be “substantially identical.”This definition also refers to, or may be applied to, the compliment ofa test sequence. The definition also includes sequences that havedeletions and/or additions, as well as those that have substitutions. Asdescribed below, the preferred algorithms can account for gaps and thelike. Preferably, identity exists over a region that is at least about10 amino acids or 20 nucleotides in length, or more preferably over aregion that is 10-50 amino acids or 20-50 nucleotides in length. As usedherein, percent (%) amino acid sequence identity is defined as thepercentage of amino acids in a candidate sequence that are identical tothe amino acids in a reference sequence, after aligning the sequencesand introducing gaps, if necessary, to achieve the maximum percentsequence identity. Alignment for purposes of determining percentsequence identity can be achieved in various ways that are within theskill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR)software. Appropriate parameters for measuring alignment, including anyalgorithms needed to achieve maximal alignment over the full-length ofthe sequences being compared can be determined by known methods.

For sequence comparisons, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Preferably,default program parameters can be used, or alternative parameters can bedesignated. The sequence comparison algorithm then calculates thepercent sequence identities for the test sequences relative to thereference sequence, based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 10 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well-known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homologyalignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970),by the search for similarity method of Pearson & Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444 (1988), by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,Wis.), or by manual alignment and visual inspection (see, e.g., CurrentProtocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

The phrase “selectively (or specifically) hybridizes to” refers to thebinding, duplexing, or hybridizing of a molecule only to a particularnucleotide sequence with a higher affinity, e.g., under more stringentconditions, than to other nucleotide sequences (e.g., total cellular orlibrary DNA or RNA).

The phrase “stringent hybridization conditions” refers to conditionsunder which a probe will hybridize to its target subsequence, typicallyin a complex mixture of nucleic acids, but to no other sequences.Stringent conditions are sequence-dependent and will be different indifferent circumstances. Longer sequences hybridize specifically athigher temperatures. An extensive guide to the hybridization of nucleicacids is found in Tijssen, Techniques in Biochemistry and MolecularBiology—Hybridization with Nucleic Probes, “Overview of principles ofhybridization and the strategy of nucleic acid assays” (1993).Generally, stringent conditions are selected to be about 5-10° C. lowerthan the thermal melting point (T_(m)) for the specific sequence at adefined ionic strength pH. The T_(m) is the temperature (under definedionic strength, pH, and nucleic concentration) at which 50% of theprobes complementary to the target hybridize to the target sequence atequilibrium (as the target sequences are present in excess, at T_(m),50% of the probes are occupied at equilibrium). Stringent conditions mayalso be achieved with the addition of destabilizing agents such asformamide. For selective or specific hybridization, a positive signal isat least two times background, preferably 10 times backgroundhybridization. Exemplary stringent hybridization conditions can be asfollowing: 50% formamide, 5×SSC, and 1% SDS, incubating at 42° C., or,5×SSC, 1% SDS, incubating at 65° C., with wash in 0.2×SSC, and 0.1% SDSat 65° C.

Nucleic acids that do not hybridize to each other under stringentconditions are still substantially identical if the polypeptides whichthey encode are substantially identical. This occurs, for example, whena copy of a nucleic acid is created using the maximum codon degeneracypermitted by the genetic code. In such cases, the nucleic acidstypically hybridize under moderately stringent hybridization conditions.Exemplary “moderately stringent hybridization conditions” include ahybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C.,and a wash in 1×SSC at 45° C. A positive hybridization is at least twicebackground. Those of ordinary skill will readily recognize thatalternative hybridization and wash conditions can be utilized to provideconditions of similar stringency. Additional guidelines for determininghybridization parameters are provided in numerous reference, e.g., andCurrent Protocols in Molecular Biology, ed. Ausubel, et al.

Twenty amino acids are commonly found in proteins. Those amino acids canbe grouped into nine classes or groups based on the chemical propertiesof their side chains. Substitution of one amino acid residue for anotherwithin the same class or group is referred to herein as a “conservative”substitution. Conservative amino acid substitutions can frequently bemade in a protein without significantly altering the conformation orfunction of the protein. Substitution of one amino acid residue foranother from a different class or group is referred to herein as a“non-conservative” substitution. In contrast, non-conservative aminoacid substitutions tend to modify conformation and function of aprotein.

Example of Amino Acid Classification

Small/Aliphatic residues: Gly, Ala, Val, Leu, Ile

Cyclic Imino Acid: Pro Hydroxyl-containing Residues: Ser, Thr AcidicResidues: Asp, Glu Amide Residues: Asn, Gln Basic Residues: Lys, ArgImidazole Residue: His Aromatic Residues: Phe, Tyr, TrpSulfur-containing Residues: Met, Cys

In some embodiments, the conservative amino acid substitution comprisessubstituting any of glycine (G), alanine (A), isoleucine (I), valine(V), and leucine (L) for any other of these aliphatic amino acids;serine (S) for threonine (T) and vice versa; aspartic acid (D) forglutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) andvice versa; lysine (K) for arginine (R) and vice versa; phenylalanine(F), tyrosine (Y) and tryptophan (W) for any other of these aromaticamino acids; and methionine (M) for cysteine (C) and vice versa. Othersubstitutions can also be considered conservative, depending on theenvironment of the particular amino acid and its role in thethree-dimensional structure of the protein. For example, glycine (G) andalanine (A) can frequently be interchangeable, as can alanine (A) andvaline (V). Methionine (M), which is relatively hydrophobic, canfrequently be interchanged with leucine and isoleucine, and sometimeswith valine. Lysine (K) and arginine (R) are frequently interchangeablein locations in which the significant feature of the amino acid residueis its charge and the differing pKs of these two amino acid residues arenot significant. Still other changes can be considered “conservative” inparticular environments (see, e.g., BIOCHEMISTRY at pp. 13-15, 2nd ed.Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat'lAcad. Sci. USA (1992) 89:10915-10919; Lei et al., J. Biol. Chem. (1995)270(20):11882-11886).

“Polypeptide,” “peptide,” and “protein” are used herein interchangeablyand mean any peptide-linked chain of amino acids, regardless of lengthor post-translational modification. As noted below, the polypeptidesdescribed herein can be, e.g., wild-type proteins, biologically-activefragments of the wild-type proteins, or variants of the wild-typeproteins or fragments. Variants, in accordance with the disclosure, cancontain amino acid substitutions, deletions, or insertions. Thesubstitutions can be conservative or non-conservative.

Following expression, the proteins can be isolated. The term “purified”or “isolated” as applied to any of the proteins described herein refersto a polypeptide that has been separated or purified from components(e.g., proteins or other naturally-occurring biological or organicmolecules) which naturally accompany it, e.g., other proteins, lipids,and nucleic acid in a cell expressing the proteins. Typically, apolypeptide is purified when it constitutes at least 60 (e.g., at least65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the totalprotein in a sample.

An amino acid residue in a protein “corresponds” to a given residue whenit occupies the same essential structural position within the protein asthe given residue. For example, a selected residue in a selected proteincorresponds to Cys784 of human androgen receptor when the selectedresidue occupies the same essential spatial or other structuralrelationship as Cys 784 in human androgen receptor. In some embodiments,where a selected protein is aligned for maximum homology with the humanandrogen receptor protein, the position in the aligned selected proteinaligning with Cys784 is said to correspond to Cys784. Instead of aprimary sequence alignment, a three dimensional structural alignment canalso be used, e.g., where the structure of the selected protein isaligned for maximum correspondence with the human androgen receptorprotein and the overall structures compared. In this case, an amino acidthat occupies the same essential position as Cys784 in the structuralmodel is said to correspond to the Cys784 residue.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g. anti-canceragent). The compound of the invention can be administered alone or canbe coadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation, to increasedegradation of a prodrug and release of the drug, detectable agent). Thecompositions of the present invention can be delivered by transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., reducing, eliminating, or slowing theprogression of disease symptoms (e.g. symptoms of cancer or aberrantandrogen receptor activity). Determination of a therapeuticallyeffective amount of a compound of the invention is well within thecapabilities of those skilled in the art, especially in light of thedetailed disclosure herein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g. symptoms of cancer), kind of concurrent treatment,complications from the disease being treated or other health-relatedproblems. Other therapeutic regimens or agents can be used inconjunction with the methods and compounds of Applicants' invention.Adjustment and manipulation of established dosages (e.g., frequency andduration) are well within the ability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer,or with adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent.

In embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In someembodiments, the compounds described herein may be combined withtreatments for cancer such as radiation or surgery.

A “drug-resistant estrogen receptor” is a modified (relative towildtype) estrogen receptor that is inhibited less effectively by thedrug than a wildtype estrogen receptor. A “drug-resistant human estrogenreceptor” is a modified (relative to wildtype) human estrogen receptorthat is inhibited less effectively by the drug than a wildtype humanestrogen receptor.

A “drug-resistant cancer” is a cancer that is inhibited less effectivelyby the drug than a non-drug resistant cancer. An “antiestrogen-resistantcancer” is a cancer that is inhibited less effectively by theantiestrogen than a non-antiestrogren resistant cancer. An “endocrinetherapeutic-resistant cancer” is a cancer that is inhibited lesseffectively by the endocrine therapeutic than a non-endocrinetherapeutic resistant cancer.

The term “antiestrogen” refers to a compound that binds estrogenreceptor without one or more of the estrogen receptor activitiesassociated with the binding of estrogen to the estrogen receptor. Inembodiments an antiestrogen is a compound that inhibits one or moreeffects of estrogen (e.g., on ER, on a cell, on a tissue, or on anorganism). Examples of an antiestrogen include fluvestrant, clomifene,femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene,lasofoxifene, and ospemifene.

The term “endocrine therapeutic” refers to a compound that is effectivefor modulating hormone activity in a subject. Use of an endocrinetherapeutic in treatment of a subject is “endocrine therapy”. Modulationof hormone activity by an endocrine therapeutic may include increasing,decreasing, blocking, removing, or otherwise changing the level of ahormone or the level of activity of a hormone. Examples of endocrinetherapeutics include antiestrogens, aromatase inhibitors, SERMs,fluvestrant, clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen,toremifene, lasofoxifene, ospemifene, anastrozole, letrozole,exemestane, vorozole, formestane, fadrozole, aminoglutethimide, andtestolactone.

The term “estrogen receptor” or “ER” refers to an established member ofthe nuclear receptor family of receptors which is a transcription factoractivated by binding ligands such as the hormones 17β-estradiol,estriol, estrone, etc. In embodiments, “estrogen receptor” or “ER”refers to a nuclear receptor which is a transcription factor activatedby binding ligands such as the hormones 17β-estradiol, estriol, and/orestrone. In embodiments, “estrogen receptor” or “ER” refers to a nuclearreceptor which is a transcription factor activated by binding thehormone 17β-estradiol. The term “estrogen receptor” may refer to thenucleotide sequence or protein sequence of human estrogen receptor. Theterm “estrogen receptor” may refer to the nucleotide sequence or proteinsequence of human estrogen receptor 1 (a.k.a. ER-alpha, ERalpha, or ERα)(e.g., Entrez 2099, Uniprot P03372, RefSeq NM_000125, OMIM 133430,NP_000116, NP_000116.2, NM_000125.3, GI:62821794, and/or GI: 170295798).The term “estrogen receptor” may refer to the nucleotide sequence orprotein sequence of human estrogen receptor 2 (a.k.a. ER-beta, ERbeta,or ERβ) (e.g., Entrez 2100, Uniprot Q92731, RefSeq NM_001040275, OMIM601663, and/or GI: 94538324). The term “estrogen receptor” includes boththe wild-type form of the nucleotide sequences or proteins as well asany mutants thereof. In some embodiments, “estrogen receptor” iswild-type estrogen receptor. In some embodiments, “estrogen receptor” isone or more mutant forms. The term “estrogen receptor” XYZ refers to anucleotide sequence or protein of a mutant estrogen receptor wherein theY numbered amino acid of estrogen receptor that normally has an X aminoacid in the wildtype, instead has a Z amino acid in the mutant. Inembodiments, an estrogen receptor is the wildtype human estrogenreceptor. In embodiments, an estrogen receptor is the wildtype humanERα. In embodiments, an estrogen receptor is the wildtype human ERβ. Inembodiments, an estrogen receptor is the wildtype human ERα or ERβ. Inembodiments, an estrogen receptor is the wildtype human ERα and ERβ. Inembodiments, the estrogen receptor is a mutant estrogen receptor. Inembodiments, the mutant estrogen receptor is associated with a diseasethat is not associated with wildtype estrogen receptor (e.g., drugresistant cancer). In embodiments, the estrogen receptor includes atleast one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,or 30 mutations) compared to the sequence above.

B. Compounds

In an aspect is provided a compound, or a pharmaceutically acceptablesalt thereof, having the formula:

R¹ is independently a hydrogen,

halogen, —NR²R³, —CX^(a) ₃, —CN, —SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR²R³,—NHNR²R³, —ONR²R³, —NHC═(O)NHNR²R³, —NHC═(O)NR²R³, —N(O)_(m1), —C(O)R⁹,—C(O)—OR⁹, —C(O)NR²R³, —OR¹⁰, —NR²SO₂R¹⁰, —NR²C═(O)R⁹, —NR²C(O)—OR⁹,—NR²OR⁹, —OCX^(a) ₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R² is independently a hydrogen,

halogen, —CX^(b) ₃, —CN, —SO₂Cl, —SO_(n2)R¹⁴, —SO_(v2)NR″R¹², —NHNH₂,—ONR¹¹R¹², —NHC═(O)NHNH₂, —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX^(b) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R³ is independently a hydrogen, halogen, —CX^(c) ₃, —CN, —SO₂Cl,—SO_(n3)R¹⁸, —SO₃NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁵R¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷,—C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷,—NR¹⁵OR¹⁷, —OCX^(c) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R² andR³ substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

L is independently a bond, —NR⁴—, —NR⁴C(O)—, —C(O)NR⁴—, —O—, —S—,—C(O)—, —S(O)—, —S(O)₂—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene; or a substituted or unsubstitutedspirocyclic linker.

R⁴ is independently a hydrogen,

halogen, —CX^(d) ₃, —CN, —SO₂Cl, —SO_(n4)R²², —SO_(v4)NR¹⁹R²⁰, —NHNH₂,—ONR¹⁹R²⁰, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁹R²⁰, —N(O)_(m4), —NR¹⁹R²⁰,—C(O)R²¹, —C(O)—OR²¹, —C(O)NR¹⁹R¹², —OR²², —NR¹⁹SO₂R²², —NR¹⁹C═(O)R²¹,—NR¹⁹C(O)—OR²¹, —NR¹⁹OR²¹, —OCX^(d) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²²are independently hydrogen, halogen, —CX₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹and R¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹⁵ and R¹⁶ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R¹⁹ and R²⁰ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

The symbol n is an integer from 0 to 5. The symbols m1, m2, m3, m4, v1,v2, v3, and v4 are independently 1 or 2. The symbols n1, n2, n3, and n4are independently an integer from 0 to 4. The symbols X, X^(a), X^(b),X^(c) and X^(d) are independently —Cl, —Br, —I, or —F.

In an aspect is provided a compound, or a pharmaceutically acceptablesalt thereof, having the formula:

R¹ is independently a hydrogen,

halogen, —NR²R³, —CX^(a) ₃, —CN, —SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR²R³,—NHNR²R³, —ONR²R³, —NHC═(O)NHNR²R³, —NHC═(O)NR²R³, —N(O)_(m1), —C(O)R⁹,—C(O)—OR⁹, —C(O)NR²R³, —OR¹⁰, —NR²SO₂R¹⁰, —NR²C═(O)R⁹, —NR²C(O)—OR⁹,—NR²OR⁹, —OCX^(a) ₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R² is independently a hydrogen,

halogen, —CX^(b) ₃, —CN, —SO₂Cl, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂,—ONR¹¹R¹², —NHC═(O)NHNH₂, —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹, R¹², —OR¹⁴, —NR¹¹SO₂R⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX^(b) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R³ is independently a hydrogen,

halogen, —CX^(c) ₃, —CN, —SO₂Cl, —SO_(n3)R¹⁸, —SO₃NR¹⁵R¹⁶, —NHNH₂,—ONR¹⁵R¹⁶, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁵R¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶,—C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷,—NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX^(c) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R² and R³ substituents may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl.

L is independently a bond, —NR⁴—, —NR⁴C(O)—, —C(O)NR⁴—, —O—, —S—,—C(O)—, —S(O)—, —S(O)₂—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene; or a substituted or unsubstitutedspirocyclic linker.

R⁴ is independently a hydrogen,

halogen, —CX^(d) ₃, —CN, —SO₂Cl, —SO_(n4)R²², —SO_(v4)NR¹⁹R²⁰, —NHNH₂,—ONR¹⁹R²⁰, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁹R²⁰, —N(O)_(m4), —NR¹⁹R²⁰,—C(O)R²¹, —C(O)—OR²¹, —C(O)NR¹⁹R¹², —OR²², —NR¹⁹SO₂R²², —NR¹⁹C═(O)R²¹,—NR¹⁹C(O)—OR²¹, —NR¹⁹OR²¹, —OCX^(d) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²²are independently hydrogen, halogen, —CX₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹and R¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹⁵ and R¹⁶ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R¹⁹ and R²⁰ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

The symbol n is an integer from 0 to 5. The symbols m1, m2, m3, m4, v1,v2, v3, and v4 are independently 1 or 2. The symbols n1, n2, n3, and n4are independently an integer from 0 to 4. The symbols X, X^(a), X^(b),X^(c) and X^(d) are independently —Cl, —Br, —I, or —F.

For compounds described herein, the —CH₃ as indicated by an asterisk inthe structure below, may be replaced with an unsubstituted C₁-C₁₀ alkyl:

embodiments, the —CH₃ as indicated by the asterisk may be replaced withan unsubstituted C₁-C₅ alkyl.

In embodiments, the compound has the formula:

The variables L and R¹ are as described herein.

R⁵ is independently a hydrogen,

halogen, —CX^(e) ₃, —CN, —SO₂Cl, —SO_(n5)R²⁶, —SO_(v5)NR²³R²⁴, —NHNH₂,—ONR²³R²⁴, —NHC═(O)NHNH₂, —NHC═(O)NR²³R²⁴, —N(O)_(m5), —NR²³R²⁴,—C(O)R²⁵, —C(O)—OR²⁵, —C(O)NR²³R²⁴, —OR²⁶, —NR²³SO₂R²⁶, —NR²³C═(O)R²⁵,—NR²³C(O)—OR²⁵, —NR²³OR²⁵, —OCX^(e) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

R²³, R²⁴, R²⁵, and R²⁶ are independently hydrogen,

halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R²³ and R²⁴ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

The symbols m5 and v5 are independently 1 or 2. The symbol n5 isindependently an integer from 0 to 4. The symbol X^(e) is independently—Cl, —Br, —I, or —F.

In embodiments, the compound has the formula:

The variables L and R¹ are as described herein.

In embodiments, the compound has the formula:

The variables L, n, R², and R³ are as described herein.

In embodiments, the compound has the formula:

The variables L, R², R³, and R⁵ are as described herein.

In embodiments, the compound has the formula:

The variables L, R², and R³ are as described herein.

In embodiments, R¹ is independently

halogen, —NR²R³, —CX^(a) ₃, —CN, —SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR²R³,—NHNR²R³, —ONR²R³, —NHC═(O)NHNR²R³, —NHC═(O)NR²R³, —N(O)_(m1), —C(O)R⁹,—C(O)—OR⁹, —C(O)NR²R³, —OR¹⁰, —NR²SO₂R¹⁰, —NR²C═(O)R⁹, —NR²C(O)—OR⁹,—NR²OR⁹, —OCX^(a) ₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R¹ is independently hydrogen. In embodiments, R¹ isindependently —NR²R³. In embodiments, R¹ is independently —NH₂. Inembodiments, R¹ is independently —CF₃. In embodiments, R¹ isindependently —CCl₃. In embodiments, R¹ is independently —N(O)₂. Inembodiments, R¹ is independently halogen. In embodiments, R¹ isindependently —F. In embodiments, R¹ is independently —Cl. Inembodiments, R¹ is independently —Br. In embodiments, R¹ isindependently —I. In embodiments, R¹ is independently substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R¹ is independently unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In embodiments, R¹ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹ is independently unsubstituted C₃-C₈cycloalkyl. In embodiments, R¹ is independently substituted orunsubstituted C₃-C₇ cycloalkyl. In embodiments, R¹ is independentlyunsubstituted C₃-C₇ cycloalkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹ is independently unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R¹ is independently substituted orunsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R¹ isindependently unsubstituted 3 to 7 membered heterocycloalkyl. Inembodiments, R¹ is independently substituted or unsubstituted C₆-C₁₂aryl. In embodiments, R¹ is independently unsubstituted C₆-C₁₂ aryl. Inembodiments, R¹ is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R¹ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R¹ is independently substituted or unsubstituted 5 to 10membered heteroaryl. In embodiments, R¹ is independently unsubstituted 5to 10 membered heteroaryl. In embodiments, R¹ is independentlysubstituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments,R¹ is independently unsubstituted 5 to 9 membered heteroaryl. Inembodiments, R¹ is independently piperadine. In embodiments, R¹ isindependently piperazine. In embodiments, R¹ is independently pyridine.In embodiments, R¹ is independently pyrazine. In embodiments, R¹ isindependently dimethylamino. In embodiments, R¹ is independentlydimethylaminoethyl. In embodiments, R¹ is independentlydimethylaminopropyl. In embodiments, R¹ is independentlyethylmorpholinyl. In embodiments, R¹ is independently morpholinyl.

In embodiments, R² is independently halogen, —CX^(b) ₃, —CN, —SO₂Cl,—SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹², —NHC═(O)NHNH₂,—NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹², —C(O)R¹³, —C(O)—OR¹³,—C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C(O)—OR¹³,—NR¹¹OR¹³, —OCX^(b) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R² is independently hydrogen. In embodiments, R² isindependently halogen. In embodiments, R² is independently substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

In embodiments, R² is independently substituted or unsubstituted C₁-C₁₂alkyl. In embodiments, R² is independently unsubstituted C₁-C₁₂ alkyl.In embodiments, R² is independently substituted or unsubstituted C₁-C₈alkyl. In embodiments, R² is independently unsubstituted C₁-C₈ alkyl. Inembodiments, R² is independently substituted or unsubstituted C₁-C₄alkyl. In embodiments, R² is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R² is independently unsubstituted methyl. In embodiments,R² is independently unsubstituted ethyl. In embodiments, R² isindependently unsubstituted propyl. In embodiments, R² is independentlysubstituted or unsubstituted 2 to 12 membered heteroalkyl. Inembodiments, R² is independently unsubstituted 2 to 12 memberedheteroalkyl. In embodiments, R² is independently substituted orunsubstituted 2 to 8 membered heteroalkyl. In embodiments, R² isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R² is independently substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R² is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R² is independently substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl. Inembodiments, R² is independently substituted or unsubstituted (C₁-C₁₀)alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl.

In embodiments, R³ is independently a

halogen, —CX^(c) ₃, —CN, —SO₂Cl, —SO_(n3)R¹⁸, —SO_(v3)NR¹⁵R¹⁶, —NHNH₂,—ONR¹⁵R¹⁶, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁵R¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶,—C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷,—NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX^(c) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R³ is independently hydrogen. Inembodiments, R³ is independently halogen. In embodiments, R³ isindependently substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R³ is independently substituted or unsubstituted C₁-C₁₂alkyl. In embodiments, R³ is independently unsubstituted C₁-C₁₂ alkyl.In embodiments, R³ is independently substituted or unsubstituted C₁-C₈alkyl. In embodiments, R³ is independently unsubstituted C₁-C₈ alkyl. Inembodiments, R³ is independently substituted or unsubstituted C₁-C₄alkyl. In embodiments, R³ is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R³ is independently unsubstituted methyl. In embodiments,R³ is independently unsubstituted ethyl. In embodiments, R³ isindependently unsubstituted propyl. In embodiments, R³ is independentlysubstituted or unsubstituted 2 to 12 membered heteroalkyl. Inembodiments, R³ is independently unsubstituted 2 to 12 memberedheteroalkyl. In embodiments, R³ is independently substituted orunsubstituted 2 to 8 membered heteroalkyl. In embodiments, R³ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R³ is independently substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R³ is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R³ is independently substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl. Inembodiments, R³ is independently substituted or unsubstituted (C₁-C₁₀)alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl.

In embodiments, R² and R³ substituents may optionally be joined to forma substituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. In embodiments, R² and R³ substituents arejoined to form a substituted or unsubstituted heterocycloalkyl. Inembodiments, R² and R³ substituents are joined to form an unsubstitutedheterocycloalkyl. In embodiments, R² and R³ substituents are joined toform a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R² and R³ substituents are joined to form an unsubstituted3 to 8 membered heterocycloalkyl. In embodiments, R² and R³ substituentsare joined to form a substituted or unsubstituted 3 to 7 memberedheterocycloalkyl. In embodiments, R² and R³ substituents are joined toform an unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments,R² and R³ substituents are joined to form a substituted or unsubstituted3 to 6 membered heterocycloalkyl. In embodiments, R² and R³ substituentsare joined to form an unsubstituted 3 to 6 membered heterocycloalkyl.

In embodiments, R² and R³ substituents are joined to form a substitutedor unsubstituted heteroaryl. In embodiments, R² and R³ substituents arejoined to form an unsubstituted heteroaryl. In embodiments, R² and R³substituents are joined to form a substituted or unsubstituted 5 to 10membered heteroaryl. In embodiments, R² and R³ substituents are joinedto form an unsubstituted 5 to 10 membered heteroaryl. In embodiments, R²and R³ substituents are joined to form a substituted or unsubstituted 5to 9 membered heteroaryl. In embodiments, R² and R³ substituents arejoined to form an unsubstituted 5 to 9 membered heteroaryl. Inembodiments, R² and R³ substituents are joined to form a substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R² and R³substituents are joined to form an unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R² and R substituents are joined to form

In embodiments, L is independently a

bond, —NR⁴—, —NR⁴C(O)—, —C(O)NR⁴—, —O—, —S—, —C(O)—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. In embodiments,L is independently a bond. In embodiments, L is independently —NR⁴—. Inembodiments, L is independently —NR⁴C(O)—. In embodiments, L isindependently —C(O)NR⁴—. In embodiments, L is independently —O—. Inembodiments, L is independently —S—. In embodiments, L is independently—C(O)—. In embodiments, L is independently —S(O)—. In embodiments, L isindependently —S(O)₂—. In embodiments, L is independently substituted orunsubstituted alkylene. In embodiments, L is independently unsubstitutedalkylene.

In embodiments, L is independently substituted or unsubstituted C₁-C₁₂alkylene. In embodiments, L is independently unsubstituted C₁-C₁₂alkylene. In embodiments, L is independently substituted orunsubstituted C₁-C₈ alkylene. In embodiments, L is independentlyunsubstituted C₁-C₈ alkylene. In embodiments, L is independentlysubstituted or unsubstituted C₁-C₆ alkylene. In embodiments, L isindependently unsubstituted C₁-C₆ alkylene. In embodiments, L isindependently substituted or unsubstituted C₁-C₄ alkylene. Inembodiments, L is independently unsubstituted C₁-C₄ alkylene. Inembodiments, L is independently unsubstituted methylene. In embodiments,L is independently unsubstituted ethylene. In embodiments, L isindependently unsubstituted propylene. In embodiments, L isindependently unsubstituted butylene. In embodiments, L is independentlysubstituted or unsubstituted heteroalkylene. In embodiments, L isindependently unsubstituted heteroalkylene. In embodiments, L isindependently substituted or unsubstituted 2 to 12 memberedheteroalkylene. In embodiments, L is independently unsubstituted 2 to 12membered heteroalkylene. In embodiments, L is independently substitutedor unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L isindependently unsubstituted 2 to 8 membered heteroalkylene. Inembodiments, L is independently substituted or unsubstituted 2 to 6membered heteroalkylene. In embodiments, L is independentlyunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L isindependently substituted or unsubstituted 2 to 4 memberedheteroalkylene. In embodiments, L is independently unsubstituted 2 to 4membered heteroalkylene. In embodiments, L is independently substitutedor unsubstituted cycloalkylene. In embodiments, L is independentlyunsubstituted cycloalkylene. In embodiments, L is independentlysubstituted or unsubstituted C₃-C₈ cycloalkylene. In embodiments, L isindependently C₃-C₈ cycloalkylene. In embodiments, L is independentlysubstituted or unsubstituted heterocycloalkylene. In embodiments, L isindependently unsubstituted heterocycloalkylene. In embodiments, L isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L is independently unsubstituted 3to 8 membered heterocycloalkylene. In embodiments, L is independentlysubstituted or unsubstituted arylene. In embodiments, L is independentlyunsubstituted arylene. In embodiments, L is independently substituted orunsubstituted C₆-C₁₀ arylene. In embodiments, L is independentlyunsubstituted C₆-C₁₀ arylene. In embodiments, L is independentlysubstituted or unsubstituted heteroarylene. In embodiments, L isindependently unsubstituted heteroarylene. In embodiments, L isindependently substituted or unsubstituted 5 to 10 memberedheteroarylene. In embodiments, L is independently unsubstituted 5 to 10membered heteroarylene.

In embodiments, L is independently —NH-(substituted or unsubstitutedalkylene). In embodiments, L is independently —NH-(unsubstitutedalkylene). In embodiments, L is independently —NH-(substituted orunsubstituted (C₁-C₈) alkylene). In embodiments, L is independently—NH-(unsubstituted (C₁-C₈) alkylene). In embodiments, L is independently—NH-(substituted or unsubstituted (C₁-C₄) alkylene). In embodiments, Lis independently —NH-(unsubstituted (C₁-C₄) alkylene). In embodiments, Lis independently —NH-(unsubstituted methylene). In embodiments, L isindependently —NH-(unsubstituted ethylene). In embodiments, L isindependently —NH-(unsubstituted propylene). In embodiments, L isindependently —NH-(unsubstituted butylene). In embodiments, L isindependently —NH-(unsubstituted n-propylene). In embodiments, L isindependently —NH-(unsubstituted n-butylene). In embodiments, L isindependently —NHC(O)-(substituted or unsubstituted alkylene). Inembodiments, L is independently —NHC(O)-(unsubstituted alkylene). Inembodiments, L is independently —NHC(O)-(substituted or unsubstituted(C₁-C₈) alkylene). In embodiments, L is independently—NHC(O)-(unsubstituted (C₁-C₈) alkylene). In embodiments, L isindependently —NHC(O)-(substituted or unsubstituted (C₁-C₄) alkylene).In embodiments, L is independently —NHC(O)-(unsubstituted (C₁-C₄)alkylene). In embodiments, L is independently —NHC(O)-(unsubstitutedmethylene). In embodiments, L is independently —NHC(O)-(unsubstitutedethylene). In embodiments, L is independently —NHC(O)-(unsubstitutedpropylene). In embodiments, L is independently —NHC(O)-(unsubstitutedbutylene). In embodiments, L is independently —NHC(O)-(unsubstitutedn-propylene). In embodiments, L is independently —NHC(O)-(unsubstitutedn-butylene).

In embodiments, R⁴ is independently a hydrogen,

halogen, —CX^(d) ₃, —CN, —SO₂Cl, —SO_(n4)R²², —SO_(v4)NR¹⁹R²⁰, —NHNH₂,—ONR¹⁹R²⁰, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁹R²⁰, —N(O)_(m4), —NR¹⁹R²⁰,—C(O)R²¹, —C(O)—OR²¹, —C(O)NR¹⁹R¹², —OR²², —NR¹⁹SO₂R²², —NR¹⁹C═(O)R²¹,—NR⁹C(O)—OR²¹, —NR¹⁹OR²¹, —OCX^(d) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R⁴ is independently hydrogen. Inembodiments, R⁴ is independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁴ is independently substituted or unsubstituted C₁-C₁₂alkyl. In embodiments, R⁴ is independently unsubstituted C₁-C₁₂ alkyl.In embodiments, R⁴ is independently substituted or unsubstituted C₁-C₈alkyl. In embodiments, R⁴ is independently unsubstituted C₁-C₈ alkyl. Inembodiments, R⁴ is independently substituted or unsubstituted C₁-C₄alkyl. In embodiments, R⁴ is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R⁴ is independently unsubstituted methyl. In embodiments,R⁴ is independently unsubstituted ethyl. In embodiments, R⁴ isindependently unsubstituted propyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted 2 to 12 membered heteroalkyl. Inembodiments, R⁴ is independently unsubstituted 2 to 12 memberedheteroalkyl. In embodiments, R⁴ is independently substituted orunsubstituted 2 to 8 membered heteroalkyl. In embodiments, R⁴ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R⁴ is independently substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴ is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R⁴ is independently substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl. Inembodiments, R⁴ is independently substituted or unsubstituted (C₁-C₁₀)alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl. Inembodiments, R⁴ is independently unsubstituted methyl. In embodiments,R⁴ is independently unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. Inembodiments, R⁴ is independently substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R⁴ is independently unsubstituted C₃-C₈cycloalkyl. In embodiments, R⁴ is independently substituted orunsubstituted C₃-C₇ cycloalkyl. In embodiments, R⁴ is independentlyunsubstituted C₃-C₇ cycloalkyl.

In embodiments, R⁴ is independently substituted or unsubstituted 3 to 8membered heterocycloalkyl. In embodiments, R⁴ is independentlyunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R⁴ isindependently substituted or unsubstituted 3 to 7 memberedheterocycloalkyl. In embodiments, R⁴ is independently unsubstituted 3 to7 membered heterocycloalkyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted C₆-C₁₂ aryl. In embodiments, R⁴ isindependently unsubstituted C₆-C₁₂ aryl. In embodiments, R⁴ isindependently substituted or unsubstituted C₆-C₁₀ aryl. In embodiments,R⁴ is independently unsubstituted C₆-C₁₀ aryl. In embodiments, R⁴ isindependently substituted or unsubstituted 5 to 10 membered heteroaryl.In embodiments, R⁴ is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R⁴ is independently substituted orunsubstituted 5 to 9 membered heteroaryl. In embodiments, R⁴ isindependently unsubstituted 5 to 9 membered heteroaryl.

In embodiments, R⁵ is independently a

halogen, —CX^(e) ₃, —CN, —SO₂Cl, —SO_(n5)R²⁶, —SO_(v5)NR²³R²⁴, —NHNH₂,—ONR²³R²⁴, —NHC═(O)NHNH₂, —NHC═(O)NR²³R²⁴, —N(O)_(m5), —NR²³R²⁴,—C(O)R²⁵, —C(O)—OR²⁵, —C(O)NR²³R²⁴, —OR²⁶, —NR²³SO₂R²⁶, —NR²³C═(O)R²⁵,—NR²³C(O)—OR²⁵, —NR²³OR²⁵, —OCX^(e) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R⁵ is independently hydrogen. Inembodiments, R⁵ is independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R⁵ is independently —NH₂. In embodiments, R⁵ isindependently —CF₃. In embodiments, R⁵ is independently —CCl₃. Inembodiments, R⁵ is independently —N(O)₂. In embodiments, R⁵ isindependently halogen. In embodiments, R⁵ is independently —F. Inembodiments, R⁵ is independently —Cl. In embodiments, R⁵ isindependently —Br. In embodiments, R⁵ is independently —I. Inembodiments, R⁵ is independently substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁵ is independently substituted or unsubstituted C₁-C₁₂alkyl. In embodiments, R⁵ is independently unsubstituted C₁-C₁₂ alkyl.In embodiments, R⁵ is independently substituted or unsubstituted C₁-C₈alkyl. In embodiments, R⁵ is independently unsubstituted C₁-C₈ alkyl. Inembodiments, R⁵ is independently substituted or unsubstituted C₁-C₄alkyl. In embodiments, R⁵ is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R⁵ is independently unsubstituted methyl. In embodiments,R⁵ is independently unsubstituted ethyl. In embodiments, R⁵ isindependently unsubstituted propyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted 2 to 12 membered heteroalkyl. Inembodiments, R⁵ is independently unsubstituted 2 to 12 memberedheteroalkyl. In embodiments, R⁵ is independently substituted orunsubstituted 2 to 8 membered heteroalkyl. In embodiments, R⁵ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R⁵ is independently substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R⁵ is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R⁵ is independently substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl. Inembodiments, R⁵ is independently substituted or unsubstituted (C₁-C₁₀)alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl.

In embodiments, R⁵ is independently unsubstituted cycloalkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstitutedheteroaryl. In embodiments, R⁵ is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁵ is independentlyunsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted C₃-C₇ cycloalkyl. In embodiments, R⁵ isindependently unsubstituted C₃-C₇ cycloalkyl. In embodiments, R⁵ isindependently substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁵ is independently unsubstituted 3 to8 membered heterocycloalkyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted 3 to 7 membered heterocycloalkyl. Inembodiments, R⁵ is independently unsubstituted 3 to 7 memberedheterocycloalkyl.

In embodiments, R⁵ is independently substituted or unsubstituted C₆-C₁₂aryl. In embodiments, R⁵ is independently unsubstituted C₆-C₁₂ aryl. Inembodiments, R⁵ is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R⁵ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R⁵ is independently substituted or unsubstituted 5 to 10membered heteroaryl. In embodiments, R⁵ is independently unsubstituted 5to 10 membered heteroaryl. In embodiments, R⁵ is independentlysubstituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments,R⁵ is independently unsubstituted 5 to 9 membered heteroaryl.

In embodiments, R⁵ is independently —CX^(e) ₃. In embodiments, R⁵ isindependently —CN. In embodiments, R⁵ is independently —SO₂Cl. Inembodiments, R⁵ is independently —SO_(n5)R²⁶. In embodiments, R⁵ isindependently —SO_(v5)NR²³R²⁴. In embodiments, R⁵ is independently—NHNH₂. In embodiments, R⁵ is independently —ONR²³R²⁴. In embodiments,R⁵ is independently —NHC═(O)NHNH₂. In embodiments, R⁵ is independently—NHC═(O)NR²³R²⁴. In embodiments, R⁵ is independently —N(O)_(m5). Inembodiments, R⁵ is independently —NR²³R²⁴. In embodiments, R⁵ isindependently —C(O)R²⁵. In embodiments, R⁵ is independently —C(O)—OR²⁵.In embodiments, R⁵ is independently —C(O)NR²³R²⁴. In embodiments, R⁵ isindependently —OR²⁶. In embodiments, R⁵ is independently —NR²³SO₂R²⁶. Inembodiments, R⁵ is independently —NR²³C═(O)R²⁵. In embodiments, R⁵ isindependently —NR²³C(O)—OR²⁵. In embodiments, R⁵ is independently—NR²³OR²⁵. In embodiments, R⁵ is independently —OCX^(e) ₃. Inembodiments, R⁵ is independently a hydrogen, halogen, —CX^(e) ₃, orunsubstituted alkyl. In embodiments, R⁵ is independently a hydrogen, —F,—CF₃, or unsubstituted methyl.

In embodiments, each R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸,R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, and R²⁶ are independently hydrogen,

halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ isindependently substituted or unsubstituted C₁-C₁₂ alkyl. In embodiments,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴, R²⁵, or R²⁶ is independently unsubstituted C₁-C₁₂ alkyl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted C₁-C₈ alkyl. In embodiments, R⁹, R¹⁰, R, R², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R⁹, R₁₀, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently unsubstituted C₁-C₄alkyl.

In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted 2 to 12 membered heteroalkyl. In embodiments, R⁹, R, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently unsubstituted 2 to 12 membered heteroalkyl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted 2 to 8 membered heteroalkyl. In embodiments, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently unsubstituted 2 to 8 membered heteroalkyl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R⁹, R¹⁰, R, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, r R²⁶ is independently substituted orunsubstituted alkyl or substituted or unsubstituted heteroalkyl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted (C₁-C₁₀) alkyl or substituted or unsubstituted 2 to 10membered heteroalkyl. In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ isindependently unsubstituted methyl. In embodiments, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶is independently H.

In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl. In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ isindependently substituted or unsubstituted C₃-C₈ cycloalkyl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently unsubstituted C₃-C₈cycloalkyl. In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independentlysubstituted or unsubstituted C₃-C₇ cycloalkyl. In embodiments, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴,R²⁵, or R²⁶ is independently unsubstituted C₃-C₇ cycloalkyl.

In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴,R²⁵, or R²⁶ is independently unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independentlysubstituted or unsubstituted 3 to 7 membered heterocycloalkyl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently unsubstituted 3 to 7membered heterocycloalkyl.

In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted C₆-C₁₂ aryl. In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ isindependently unsubstituted C₆-C₁₂ aryl. In embodiments, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently substituted or unsubstituted C₆-C₁₀ aryl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently unsubstituted C₆-C₁₀aryl.

In embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, or R²⁶ is independently substituted orunsubstituted 5 to 9 membered heteroaryl. In embodiments, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, orR²⁶ is independently unsubstituted 5 to 9 membered heteroaryl.

In embodiments, R¹¹ and R¹² substituents may optionally be joined toform a substituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. In embodiments, R¹¹ and R¹² substituents arejoined to form a substituted or unsubstituted heterocycloalkyl. Inembodiments, R¹¹ and R¹² substituents are joined to form anunsubstituted heterocycloalkyl. In embodiments, R¹¹ and R¹² substituentsare joined to form a substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R¹¹ and R¹² substituents are joined toform an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments,R¹¹ and R¹² substituents are joined to form a substituted orunsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R¹¹ andR¹² substituents are joined to form an unsubstituted 3 to 7 memberedheterocycloalkyl. In embodiments, R¹¹ and R¹² substituents are joined toform a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹¹ and R¹² substituents are joined to form anunsubstituted 3 to 6 membered heterocycloalkyl.

In embodiments, R¹¹ and R¹² substituents are joined to form asubstituted or unsubstituted heteroaryl. In embodiments, R¹¹ and R¹²substituents are joined to form an unsubstituted heteroaryl. Inembodiments, R¹¹ and R¹² substituents are joined to form a substitutedor unsubstituted 5 to 10 membered heteroaryl. In embodiments, R¹¹ andR¹² substituents are joined to form an unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R¹¹ and R¹² substituents are joined to forma substituted or unsubstituted 5 to 9 membered heteroaryl. Inembodiments, R¹¹ and R¹² substituents are joined to form anunsubstituted 5 to 9 membered heteroaryl. In embodiments, R¹¹ and R¹²substituents are joined to form a substituted or unsubstituted 5 to 6membered heteroaryl.

In embodiments, R¹⁵ and R¹⁶ substituents may optionally be joined toform a substituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. In embodiments, R¹⁵ and R¹⁶ substituents arejoined to form a substituted or unsubstituted heterocycloalkyl. Inembodiments, R⁵ and R¹⁶ substituents are joined to form an unsubstitutedheterocycloalkyl. In embodiments, R¹⁵ and R¹⁶ substituents are joined toform a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹⁵ and R¹⁶ substituents are joined to form anunsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R¹⁵ andR¹⁶ substituents are joined to form a substituted or unsubstituted 3 to7 membered heterocycloalkyl. In embodiments, R¹⁵ and R¹⁶ substituentsare joined to form an unsubstituted 3 to 7 membered heterocycloalkyl. Inembodiments, R¹⁵ and R¹⁶ substituents are joined to form a substitutedor unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹⁵and R¹⁶ substituents are joined to form an unsubstituted 3 to 6 memberedheterocycloalkyl.

In embodiments, R¹⁵ and R¹⁶ substituents are joined to form asubstituted or unsubstituted heteroaryl. In embodiments, R⁵ and R¹⁶substituents are joined to form an unsubstituted heteroaryl. Inembodiments, R¹⁵ and R¹⁶ substituents are joined to form a substitutedor unsubstituted 5 to 10 membered heteroaryl. In embodiments, R¹⁵ andR¹⁶ substituents are joined to form an unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R¹⁵ and R¹⁶ substituents are joined to forma substituted or unsubstituted 5 to 9 membered heteroaryl. Inembodiments, R¹⁵ and R¹⁶ substituents are joined to form anunsubstituted 5 to 9 membered heteroaryl. In embodiments, R¹⁵ and R¹⁶substituents are joined to form a substituted or unsubstituted 5 to 6membered heteroaryl.

In embodiments, R¹⁹ and R²⁰ substituents may optionally be joined toform a substituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. In embodiments, R¹⁹ and R²⁰ substituents arejoined to form a substituted or unsubstituted heterocycloalkyl. Inembodiments, R¹⁹ and R²⁰ substituents are joined to form anunsubstituted heterocycloalkyl. In embodiments, R¹⁹ and R²⁰ substituentsare joined to form a substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R¹⁹ and R²⁰ substituents are joined toform an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments,R¹⁹ and R²⁰ substituents are joined to form a substituted orunsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R¹⁹ andR²⁰ substituents are joined to form an unsubstituted 3 to 7 memberedheterocycloalkyl. In embodiments, R¹⁹ and R²⁰ substituents are joined toform a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹⁹ and R²⁰ substituents are joined to form anunsubstituted 3 to 6 membered heterocycloalkyl.

In embodiments, R¹⁹ and R²⁰ substituents are joined to form asubstituted or unsubstituted heteroaryl. In embodiments, R¹⁹ and R²⁰substituents are joined to form an unsubstituted heteroaryl. Inembodiments, R¹⁹ and R²⁰ substituents are joined to form a substitutedor unsubstituted 5 to 10 membered heteroaryl. In embodiments, R¹⁹ andR²⁰ substituents are joined to form an unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R¹⁹ and R²⁰ substituents are joined to forma substituted or unsubstituted 5 to 9 membered heteroaryl. Inembodiments, R¹⁹ and R²⁰ substituents are joined to form anunsubstituted 5 to 9 membered heteroaryl. In embodiments, R¹⁹ and R²⁰substituents are joined to form a substituted or unsubstituted 5 to 6membered heteroaryl.

In embodiments, R²³ and R²⁴ substituents may optionally be joined toform a substituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. In embodiments, R²³ and R²⁴ substituents arejoined to form a substituted or unsubstituted heterocycloalkyl. Inembodiments, R²³ and R²⁴ substituents are joined to form anunsubstituted heterocycloalkyl. In embodiments, R²³ and R²⁴ substituentsare joined to form a substituted or unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R²³ and R²⁴ substituents are joined toform an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments,R²³ and R²⁴ substituents are joined to form a substituted orunsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R²³ andR²⁴ substituents are joined to form an unsubstituted 3 to 7 memberedheterocycloalkyl. In embodiments, R²³ and R²⁴ substituents are joined toform a substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²³ and R²⁴ substituents are joined to form anunsubstituted 3 to 6 membered heterocycloalkyl.

In embodiments, R²³ and R²⁴ substituents are joined to form asubstituted or unsubstituted heteroaryl. In embodiments, R²³ and R²⁴substituents are joined to form an unsubstituted heteroaryl. Inembodiments, R²³ and R²⁴ substituents are joined to form a substitutedor unsubstituted 5 to 10 membered heteroaryl. In embodiments, R²³ andR²⁴ substituents are joined to form an unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R²³ and R²⁴ substituents are joined to forma substituted or unsubstituted 5 to 9 membered heteroaryl. Inembodiments, R²³ and R²⁴ substituents are joined to form anunsubstituted 5 to 9 membered heteroaryl. In embodiments, R²³ and R²⁴substituents are joined to form a substituted or unsubstituted 5 to 6membered heteroaryl.

In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2.In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, m2is 1. In embodiments, m2 is 2. In embodiments, m3 is 1. In embodiments,m3 is 2. In embodiments, m4 is 1. In embodiments, m4 is 2. Inembodiments, m5 is 1. In embodiments, m5 is 2. In embodiments, v1 is 1.In embodiments, v1 is 2. In embodiments, v2 is 1. In embodiments, v2 is2. In embodiments, v3 is 1. In embodiments, v3 is 2. In embodiments, v4is 1. In embodiments, v4 is 2. In embodiments, v5 is 1. In embodiments,v5 is 2. In embodiments, n1 is 0. In embodiments, n1 is 1. Inembodiments, n1 is 2. In embodiments, n1 is 3. In embodiments, n1 is 4.In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is2. In embodiments, n2 is 3. In embodiments, n2 is 4. In embodiments, n3is 0. In embodiments, n3 is 1. In embodiments, n3 is 2. In embodiments,n3 is 3. In embodiments, n3 is 4. In embodiments, n4 is 0. Inembodiments, n4 is 1. In embodiments, n4 is 2. In embodiments, n4 is 3.In embodiments, n4 is 4. In embodiments, n5 is 0. In embodiments, n5is 1. In embodiments, n5 is 2. In embodiments, n5 is 3. In embodiments,n5 is 4.

In embodiments, X is independently —Cl. In embodiments, X isindependently —Br. In embodiments, X is independently —I. Inembodiments, X is independently —F. In embodiments, X^(a) isindependently —Cl. In embodiments, X^(a) is independently —Br. Inembodiments, X^(a) is independently —I. In embodiments, X^(a) isindependently —F. In embodiments, X^(b) is independently —Cl. Inembodiments, X^(b) is independently —Br. In embodiments, X^(b) isindependently —I. In embodiments, X^(b) is independently —F. Inembodiments, X^(c) is independently —Cl. In embodiments, X^(c) isindependently —Br. In embodiments, X^(c) is independently —I. Inembodiments, X^(c) is independently —F. In embodiments, X^(d) isindependently —Cl. In embodiments, X^(d) is independently —Br. Inembodiments, X^(d) is independently —I. In embodiments, X^(d) isindependently —F. In embodiments, X^(e) is independently —Cl. Inembodiments, X^(e) is independently —Br. In embodiments, X^(e) isindependently —I. In embodiments, X^(e) is independently —F.

In embodiments, R¹ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R²⁷-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR²⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R²⁷ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R²⁸-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR²⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²⁷ is piperadine. In embodiments, R²⁷ is piperazine. Inembodiments, R²⁷ is pyridine. In embodiments, R²⁷ is pyrazine. Inembodiments, R²⁷ is dimethylamino. In embodiments, R²⁷ isdimethylaminoethyl. In embodiments, R²⁷ is dimethylaminopropyl. Inembodiments, R²⁷ is ethylmorpholinyl. In embodiments, R²⁷ ismorpholinyl.

R²⁸ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R²⁹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R²⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R²⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R²⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R²⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR²⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).In embodiments, R²⁸ is piperadine. In embodiments, R²⁸ is piperazine. Inembodiments, R²⁸ is pyridine. In embodiments, R²⁸ is pyrazine. Inembodiments, R²⁸ is dimethylamino. In embodiments, R²⁸ isdimethylaminoethyl. In embodiments, R²⁸ is dimethylaminopropyl. Inembodiments, R²⁸ is ethylmorpholinyl. In embodiments, R²⁸ ismorpholinyl.

In embodiments, R² is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁰-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁰-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁰ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³¹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³¹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³¹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³¹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³¹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R³¹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³²-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³²-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R³ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³³-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³³-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³³-substituted or unsubstituted aryl (e.g. 6 to 12 membered aryl or 6membered aryl), or R³³ substituted or unsubstituted heteroaryl (e.g. 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

R³³ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁴-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁴-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁴ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁵-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁵-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁵-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁵-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁴ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁶-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁶ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁷-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁷ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁸-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁵ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁰-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁰-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴⁰ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴¹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴¹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴¹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴¹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴¹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁹ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴²-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴²-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴² is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴³-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴³-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴³-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴³-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴³ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁴-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁴-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁰ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁵-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁵-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁵-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁵-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴⁵ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁶-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴⁶ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁷-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹¹ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁸-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴⁸ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁴⁹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁴⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴⁹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁰-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁰-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹² is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵¹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵¹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵¹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R^(s5)-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl),or R^(s1)-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵¹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵²-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵²-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵² is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵³-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵³-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵³-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵³-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹³ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁴-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁴-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵⁴ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁵-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁵-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁵-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁵-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵⁵ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁶-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁴ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁷-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵⁷ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁸-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁵⁸ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁵⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In some embodiments, R¹⁵ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁰-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁰-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶⁰ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶¹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶¹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶¹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶¹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶¹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶¹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶²-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶²-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁶ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶³-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶³-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶³-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶³-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶³ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁴-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁴-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶⁴ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁵-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁵-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁵-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁵-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁷ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁶-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶⁶ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁷-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶⁷ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁸-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R^(s8) is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶⁹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁶⁹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁰-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁰-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁰-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁰-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁷⁰ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷¹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷¹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷¹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷¹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷¹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R¹⁹ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷²-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷²-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁰ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷³-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷³-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷³-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷³-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²¹ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁴-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁴-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²² is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁵-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁵-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁵-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁵-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²³ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁶-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁴ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁷-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁵ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁸-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R²⁶ is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷⁹-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁷⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, L is independently a bond, R⁵⁰-substituted orunsubstituted alkylene, R⁵⁰-substituted or unsubstituted heteroalkylene,R⁵⁰-substituted or unsubstituted cycloalkylene, R⁵⁰-substituted orunsubstituted heterocycloalkylene, R⁵⁰-substituted or unsubstitutedarylene, or R⁵⁰-substituted or unsubstituted heteroarylene.

R²⁹, R³², R³⁵, R³⁸, R⁴¹, R⁴⁴, R⁴⁷, R⁵⁰, R⁵³, R⁵⁶, R⁵⁹, R⁶², R⁶⁵, R⁶⁸,R⁷¹, R⁷², R⁷³, R⁷⁴, R⁷⁵, R⁷⁶, R⁷⁷, R⁷⁸, R⁷⁹, and R⁸⁰ are independentlyoxo,

halogen, —F, —Cl, —Br, —I, —CF₃, —CCl₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),unsubstituted heteroalkyl (e.g. 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstitutedcycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orunsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, the compound is

In embodiments, the compound is a compound described herein. In someembodiments, the compound is a compound selected from JD101 to JD160(e.g., JD101, JD102, JD103, JD104, JD105, JD106, JD107, JD108, JD109,JD110, JD111, JD112, JD113, JD114, JD115, JD116, JD117, JD118, JD119,JD120, JD121, JD122, JD123, JD124, JD125, JD126, JD127, JD128, JD129,JD130, JD131, JD132, JD133, JD134, JD135, JD136, JD137, JD138, JD139,JD140, JD141, JD142, JD143, JD144, JD145, JD146, JD147, JD148, JD149,JD150, JD151, JD152, JD153, JD154, JD155, JD156, JD157, JD158, JD159, orJD160). In embodiments, the compound is not a compound selected fromJD101 to JD160 (e.g., JD101, JD102, JD103, JD104, JD105, JD106, JD107,JD108, JD109, JD110, JD111, JD112, JD113, JD114, JD115, JD116, JD117,JD118, JD119, JD120, JD121, JD122, JD123, JD124, JD125, JD126, JD127,JD128, JD129, JD130, JD131, JD132, JD133, JD134, JD135, JD136, JD137,JD138, JD139, JD140, JD141, JD142, JD143, JD144, JD145, JD146, JD147,JD148, JD149, JD150, JD151, JD152, JD153, JD154, JD155, JD156, JD157,JD158, JD159, or JD160).

In some embodiments, a compound as described herein may include multipleinstances of R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰, R¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, m1, m2, m3, m4, m5,v1, v2, v3, v4, v5, n1, n2, n3, n4, n5, X, X^(a), X^(b), X^(c), X^(d)and X^(e), and/or other variables. In such embodiments, each variablemay optional be different and be appropriately labeled to distinguisheach group for greater clarity. For example, where each R¹, R², R³, R⁴,R⁵, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴, R²⁵, R²⁶, m1, m2, m3, m4, m5, v1, v2, v3, v4, v5, n1, n2, n3,n4, n5, X, X^(a), X^(b), X^(c), X^(d) and X^(e), is different, they maybe referred to, for example, as R^(1.1), R^(1.2), R^(1.3), R^(1.4),R^(1.5), R^(2.1), R^(2.2), R^(2.3), R^(2.4), R^(2.5), R^(3.1), R^(3.2),R^(3.3), R^(3.4), R^(3.5), R^(4.1), R^(4.2), R^(4.3), R^(4.4), R^(4.5),R^(5.1), R^(5.2), R^(5.3), R^(5.4), R^(5.5), R^(9.1), R^(9.2), R^(9.3),R^(9.4), R^(9.5), R^(10.1), R^(10.2), R^(10.3), R^(10.4), R^(10.5),R^(11.1), R^(11.2), R^(11.3), R^(11.4), R^(11.5), R^(12.1), R^(12.2),R^(12.3), R^(12.4), R^(12.5), R^(13.1), R^(13.2), R^(13.3), R^(13.4),R^(13.5), R^(14.1), R^(14.2), R^(14.3), R^(14.4), R^(14.5), R^(15.1),R^(15.2), R^(15.3), R^(15.4), R^(15.5), R^(16.1), R^(16.2), R^(16.3),R^(16.4), R^(16.5), R^(17.1), R^(17.2), R^(17.3), R^(17.4), R^(17.5),R^(18.1), R^(18.2), R^(18.3), R^(18.4), R^(18.5), R^(19.1), R^(19.2),R^(19.3), R^(19.4), R^(19.5), R^(20.1), R^(20.2), R^(20.4), R^(20.5),R^(21.1), R^(21.2), R^(21.3), R^(21.4), R^(21.5), R^(22.1), R^(22.2),R^(22.3), R^(22.4), R^(22.5), R^(23.1), R^(23.2), R^(23.3), R^(23.4),R^(23.5), R^(24.1), R^(24.2), R^(24.3), R^(24.4), R^(24.5), R^(25.1),R^(25.2), R^(25.3), R^(25.4), R^(25.5), R^(26.1), R^(26.2), R^(26.3),R^(26.4), R^(26.5), m1¹, m1², m1³, m1⁴, m1⁵, m2¹, m2², m2³, m2⁴, m2⁵,m3¹, m3², m3³, m3⁴, m3⁵, m4¹, m4², m4³, m4⁴, m4⁵, m5¹, m5², m5³, m5⁴,m5⁵, m1¹, m1², m1³, m1⁴, v1⁵, m2¹, v2², v2³, v2⁴, v2⁵, m3¹, v3², v3³,m3⁴, v3⁵, v4, m4², m4³, m4⁴, v4, v5, m5², m5³, v5⁴, v5⁵, n1, n1², n1³,n1⁴, n1⁵, m2¹, m2², n2³, n2⁴, m2⁵, m3¹, n3², n3³, n3⁴, n3⁵, n4¹, n4²,n4³, n4⁴, n4⁵, n5¹, n5², n5³, n5⁴, n5⁵, X¹, X², X³, X⁵, X^(a1), X^(a)X²,X^(a3), X^(a4), X^(a5), X^(b1), X^(b2), X^(b3), X^(b4), X^(b5), X^(c1),X^(c2), X^(c3), X^(c4), X^(c5), X^(d1), X^(d2), X^(d3), X^(d4), X^(d5),X^(e1), X^(e2), X^(e3), X^(e4), and/or X^(e5), respectively, wherein thedefinition of R¹ is assumed by R^(1.1), R^(1.2), R^(1.3), R^(1.4),and/or R^(1.5), wherein the definition of R² is assumed by R^(2.1),R^(2.2), R^(2.3), R^(2.4), and/or R^(2.5), wherein the definition of R³is assumed by R^(3.1), R^(3.2), R^(3.3), R^(3.4), and/or R^(3.5),wherein the definition of R⁴ is assumed by R^(4.1), R^(4.2), R^(4.3),R^(4.4), and/or R^(4.5), wherein the definition of R⁵ is assumed byR^(5.1), R^(5.2), R^(5.3), R^(5.4), and/or R^(5.5), wherein thedefinition of R⁹ is assumed by R^(9.1), R^(9.2), R^(9.3), R^(9.4),and/or R^(9.5), wherein the definition of R¹⁰ is assumed by R^(10.1),R^(10.2), R^(10.3), R^(10.4), and/or R^(10.5), wherein the definition ofR¹¹ is assumed by R^(11.1), R^(11.2), R^(11.3), R^(11.4), and/orR^(11.5), wherein the definition of R² is assumed by R^(12.1), R^(12.2),R^(12.3), R^(12.4), and/or R^(12.5), wherein the definition of R¹³ isassumed by R^(13.1), R^(13.2), R^(13.3), R^(13.4), and/or R^(13.5),wherein the definition of R¹⁴ is assumed by R^(14.1), R^(14.2),R^(14.3), R^(14.4), and/or R^(14.5), wherein the definition of R¹⁵ isassumed by R^(15.1), R^(15.2), R^(15.3), R^(15.4), and/or R^(15.5),wherein the definition of R¹⁶ is assumed by R^(16.1), R^(16.2),R^(16.3), R^(16.4), and/or R^(16.5), wherein the definition of R¹⁷ isassumed by R^(17.1), R^(17.2), R^(17.3), R^(17.4), and/or R^(17.5),wherein the definition of R¹⁸ is assumed by R^(18.1), R^(18.2),R^(18.3), R^(18.4), and/or R^(18.5), wherein the definition of R¹⁹ isassumed by R^(19.1), R^(19.2), R^(19.3), R^(19.4), and/or R^(19.5),wherein the definition of R²⁰ is assumed by R^(20.1), R^(20.2),R^(20.3), R^(20.4), and/or R^(20.5), wherein the definition of R²¹ isassumed by R^(21.1), R^(21.2), R^(21.3), R^(21.4), and/or R^(21.5),wherein the definition of R²² is assumed by R^(22.1), R^(22.2),R^(22.3), R^(22.4), and/or R^(22.5), wherein the definition of R²³ isassumed by R^(23.1), R^(23.2), R^(23.3), R^(23.4), and/or R^(23.5),wherein the definition of R²⁴ is assumed by R^(24.1), R^(24.2),R^(24.3), R^(24.4), and/or R^(24.5), wherein the definition of R²⁵ isassumed by R²⁵¹, R^(25.2), R^(25.3), R^(25.4), and/or R^(25.5), whereinthe definition of R²⁶ is assumed by R^(26.1), R^(26.2), R^(26.3),R^(26.4), and/or R^(26.5), wherein the definition of m1 is assumed bym1¹, m1², m1³, m1⁴, and/or m1⁵, wherein the definition of m2 is assumedby m2¹, m2², m2³, m2⁴, and/or m2⁵, wherein the definition of m3 isassumed by m3¹, m3², m3³, m3⁴, and/or m3⁵, wherein the definition of m4is assumed by m4¹, m4², m4³, m4⁴, and/or m4⁵, wherein the definition ofm5 is assumed by m5¹, m5², m5³, m5⁴, and/or m5⁵, wherein the definitionof v1 is assumed by v1¹, v1², V1³, V1⁴, and/or m1⁵, wherein thedefinition of v2 is assumed by v2¹, v2², v2³, v2⁴, and/or v2⁵, whereinthe definition of v3 is assumed by m3¹, m3², v3³, v3⁴, and/or v3⁵,wherein the definition of v4 is assumed by v4¹, v4², v4³, v4⁴, and/orv4⁵, wherein the definition of v5 is assumed by v5¹, v5², v5³, v5⁴,and/or v5⁵, wherein the definition of n1 is assumed by n1¹, n1², n1³,m1⁴, and/or n1⁵, wherein the definition of n2 is assumed by n2¹, n2²,n2³, n2⁴, and/or n2⁵, wherein the definition of n3 is assumed by n3¹,n3², n3³, n3⁴, and/or n3⁵, wherein the definition of n4 is assumed bym4¹, m4², n4³, n4⁴, and/or n4⁵, wherein the definition of n5 is assumedby m5¹, m5², n5³, n5⁴, and/or n5⁵, wherein the definition of X isassumed by X¹, X², X³, X⁴, and/or X⁵, wherein the definition of X^(a) isassumed by X^(a1), X^(a)X², X^(a3), X^(a4), and/or X^(a5), wherein thedefinition of X^(b) is assumed by X^(b1), X^(b2), X^(b3), X^(b4), and/orX^(b5), wherein the definition of X^(c) is assumed by X^(c1), X^(c2),X^(c3), X^(c4), and/or X^(c5), wherein the definition of X^(d) isassumed by X^(d1), X^(d2), X^(d3), X^(d4), and/or X^(d5), wherein thedefinition of X^(e) is assumed by X^(e1), X^(e2), X^(e3), X^(e4), and/orX^(e5). The variables used within a definition of R¹, R², R³, R⁴, R⁵,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴, R²⁵, R²⁶, m1, m2, m3, m4, m5, v1, v2, v3, v4, v5, n1, n2, n3,n4, n5, X, X^(a), X^(b), X^(°), X^(d) and X^(e), and/or other variablesthat appear at multiple instances and are different may similarly beappropriately labeled to distinguish each group for greater clarity.

In embodiments, the compound competes with estrogen for binding toestrogen receptor (ER). In embodiments, the compound competes with4-hydroxy tamoxifen for binding to ER. In embodiments, the compoundbinds the ligand binding domain of ER. In embodiments, the compoundmodulates the conformation of helix 12 of ER relative to theconformation of helix 12 when estrogen is bound to ER. In embodiments,the compound modulates (e.g., reduces relative to estrogen bound ER) thebinding of ER to estrogen response elements. In embodiments, thecompound modulates (e.g., reduces relative to estrogen bound ER) thephosphorylation of ER. In embodiments, the compound modulates (e.g.,reduces relative to estrogen bound ER) the activity of a cellularpathway (e.g., ras-MAPK containing pathway, PI3K/AKT containing pathway,She containing pathway, Src kinase containing pathway, JAK/STATcontaining pathway, nitric oxide synthase pathway, VEGF secretionpathway). In embodiments, the compound modulates (e.g., reduces relativeto estrogen bound ER) DNA synthesis. In embodiments, the compoundmodulates (e.g., reduces relative to estrogen bound ER) cell growth. Inembodiments, the compound modulates (e.g., reduces relative to estrogenbound ER) cell proliferation. In embodiments, the compound modulates(e.g., reduces relative to estrogen bound ER) epithelial cellproliferation. In embodiments, the compound modulates (e.g., increasesrelative to estrogen bound ER) the degradation of ER. In embodiments,the compound modulates (e.g., increases relative to estrogen bound ER)the ubiquitination of ER. In embodiments, the compound modulates (e.g.,increases relative to estrogen bound ER) the degration of ER by theproteasome.

In embodiments, the compounds set forth herein are provided aspharmaceutical compositions including the compound and apharmaceutically acceptable excipient.

C. Pharmaceutical Compositions

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, as described herein, includingembodiments (e.g. compound of formula I, Ia, Ib, II, IIa, IIb, or anyembodiment thereof, or in an example, table, figure, or claim). Inembodiments, the compound is a compound selected from JD101 to JD160. Inembodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, as described herein, isincluded in a therapeutically effective amount.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent) in atherapeutically effective amount. In embodiments of the pharmaceuticalcompositions, the second agent is an agent for treating cancer. Inembodiments of the pharmaceutical compositions, the second agent is anagent for treating a hyperproliferative disorder. In embodiments, thesecond agent is an anti-cancer agent. In embodiments, the second agentis a chemotherapeutic. In embodiments, the second agent is an agent fortreating breast cancer. In embodiments, the second agent is an agent fortreating lung cancer. In embodiments, the second agent is an agent fortreating a gynecological cancer. In embodiments, the second agent is anagent for treating ovarian cancer. In embodiments, the second agent isan agent for treating endometrial cancer. In embodiments, the secondagent is an agent for treating prostate cancer. In embodiments, thesecond agent is an agent for treating lymphangioleiomyomatosis. Inembodiments, the second agent is an agent for inhibiting estrogenreceptor activity. In embodiments, the second agent is an agent fortreating a disease associated with estrogen receptor activity. Inembodiments, the second agent is an antiestrogen. In embodiments, thesecond agent is an aromatase inhibitor. In embodiments, the second agentis a HER-2 inhibitor. In embodiments, the second agent is Herceptin. Inembodiments, the second agent is fulvestrant, clomifene, femarelle,ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene,ospemifene, anastrozole, letrozole, exemestane, vorozole, formestane,fadrozole, aminoglutethimide, or testolactone. In embodiments, thesecond agent is tamoxifen. In embodiments, the second agent is an EGFRinhibitor (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab(Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib(Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272,pelitinib/EKB—569, BMS-599626, TAK-285, CUDC-101, OSI-420/desmethylerlotinib, CP-724714, dacomitinib/PF299804, AG-490, AG-1478, AST-1306,WZ3146, AZD8931,/sapitinib, PD153035, icotinib, ARRY334543/varlitinib,ARRY-380, AEE788, WZ8040, WZ4002, or XL647).

D. Methods of Treatment

In an aspect is provided a method of treating a hyperproliferativedisorder in a subject in need thereof, including administering to thesubject an effective amount of a compound described herein.

In an aspect is provided use of a compound as described herein in themanufacture of a medicament for the treatment of a hyperproliferativedisorder in a subject in need of such treatment.

In an aspect is provided a compound as described herein for use in thetreatment of a hyperproliferative disorder in a subject in need of suchtreatment. The use includes administering to the subject a compounddescribed herein. The use may include administering to the subject atherapeutically effective amount of a compound described herein.

In embodiments, the hyperproliferative disorder is associated withestrogen receptor activity. In embodiments, the hyperproliferativedisorder is lymphangioleiomyomatosis. In embodiments, thehyperproliferative disorder is a cancer. In embodiments, thehyperproliferative disorder is a cancer resistant to an anti-canceragent (e.g., tamoxifen, an antiestrogen, an aromatase inhibitor). Inembodiments, the cancer is breast cancer. In embodiments, the cancer isER positive breast cancer. In embodiments, the cancer is ER negativebreast cancer. In embodiments, the cancer is hormone sensitive breastcancer. In embodiments, the cancer is hormone insensitive breast cancer.In embodiments, the cancer is triple negative breast cancer. Inembodiments, the cancer is HER-2 positive breast cancer. In embodiments,the cancer is metastatic breast cancer. In embodiments, the cancer islung cancer. In embodiments, the cancer is a gynecological cancer. Inembodiments, the cancer is ovarian cancer. In embodiments, the cancer isendometrial cancer. In embodiments, the cancer is prostate cancer. Inembodiments, the cancer is metastatic cancer. In embodiments, thehyperproliferative disorder (e.g., cancer) is resistant to anantiestrogen. In embodiments, the hyperproliferative disorder (e.g.,cancer) is resistant to an endocrine therapy. In embodiments, thehyperproliferative disorder (e.g., cancer) is resistant to an aromataseinhibitor. In embodiments, the hyperproliferative disorder (e.g.,cancer) is a cancer of an estrogen target organ or tissue. Inembodiments, the cancer is non-small cell lung cancer. In embodiments,the cancer is small cell lung cancer. In embodiments, the lung cancer isadenocarcinoma. In embodiments, the lung cancer is squamous-cellcarcinoma. In embodiments, the lung cancer is large-cell carcinoma. Inembodiments, the lung cancer is bronchioloalveolar carcinoma. Inembodiments, the lung cancer is stage I. In embodiments, the lung canceris stage II. In embodiments, the lung cancer is stage III. Inembodiments, the lung cancer is stage IV.

In embodiments of the method or use, the method or use includesadministering a second agent (e.g. therapeutic agent). In embodiments ofthe method or use, the method or use includes administering a secondagent (e.g. therapeutic agent) in a therapeutically effective amount. Inembodiments of the method or use, the second agent is an agent fortreating cancer. In embodiments of the method or use, the second agentis an agent for treating a hyperproliferative disorder. In embodiments,the second agent is an anti-cancer agent. In embodiments, the secondagent is a chemotherapeutic. In embodiments, the second agent is anagent for treating breast cancer. In embodiments, the second agent is anagent for treating lung cancer. In embodiments, the second agent is anagent for treating a gynecological cancer. In embodiments, the secondagent is an agent for treating ovarian cancer. In embodiments, thesecond agent is an agent for treating endometrial cancer. Inembodiments, the second agent is an agent for treating prostate cancer.In embodiments, the second agent is an agent for treatinglymphangioleiomyomatosis (LAM). In embodiments, the second agent is anagent for inhibiting estrogen receptor activity. In embodiments, thesecond agent is an agent for treating a disease associated with estrogenreceptor activity. In embodiments, the second agent is an antiestrogen.In embodiments, the second agent is an aromatase inhibitor. Inembodiments, the second agent is an endocrine therapeutic. Inembodiments, the second agent is an anti-cancer agent. In embodiments,the second agent is a chemotherapeutic. In embodiments, the second agentis a HER-2 inhibitor. In embodiments, the second agent is fulvestrant,clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene,lasofoxifene, ospemifene, anastrozole, letrozole, exemestane, vorozole,formestane, fadrozole, aminoglutethimide, or testolactone. Inembodiments, the second agent is tamoxifen. In embodiments, the methodor use does not include an increased risk of endometrial cancer. Inembodiments, the method or use does not include an increased risk of agynecological cancer. In embodiments, the method or use does not includea reduction in bone health.

In an aspect is provided a compound as described herein for use in thetreatment of gynecomastia in a subject in need of such treatment. Theuse includes administering to the subject a compound described herein.The use may include administering to the subject a therapeuticallyeffective amount of a compound described herein.

In embodiments, gynecomastia is associated with estrogen receptoractivity. In embodiments, gynecomastia is non-physiologic gynecomastia.In embodiments, gynecomastia is physiologic gynecomastia.

In embodiments, the method or use improves (e.g. increases) bone densityrelative to the absence of the compound. In embodiments, the method oruse improves (e.g. increases) bone mass relative to the absence of thecompound. In embodiments, the method or use improves (e.g. increases)bone health relative to the absence of the compound. In embodiments, themethod or use is a treatment for osteoporosis, osteogenesis imperfecta,or osteopenia. In embodiments, the method or use is a treatment forosteogenesis imperfecta.

In embodiments, the method or use is used to prevent bone deterioration,prevent bone degradation, prevent bone degeneration, prevent loss ofbone mass, prevent loss of bone density, stabilize bone deterioration,stabilize bone degradation, stabilize bone degeneration, stabilize theloss of bone mass, stabilize the loss of bone density, decrease bonedeterioration, decrease bone degradation, decrease bone degeneration,decrease loss of bone mass, decrease loss of bone density, increase bonemass, increase bone density, or combinations thereof.

In an aspect is provided a method of treating a bone disorder in asubject in need thereof, including administering to the subject aneffective amount of a compound described herein.

In an aspect is provided use of a compound as described herein in themanufacture of a medicament for the treatment of a bone disorder in asubject in need of such treatment.

In an aspect is provided a compound as described herein for use in thetreatment of a bone disorder in a subject in need of such treatment. Theuse includes administering to the subject a compound described herein.The use may include administering to the subject a therapeuticallyeffective amount of a compound described herein.

In embodiments, the bone disorder is osteoporosis, osteogenesisimperfecta, or osteopenia. In embodiments, the bone disorder isosteogenesis imperfecta. In embodiments, the bone disorder is bonedeterioration, bone degradation, bone degeneration, loss of bone mass,loss of bone density, or combinations thereof.

In embodiments, the method or use is used to prevent bone deterioration,prevent bone degradation, prevent bone degeneration, prevent loss ofbone mass, prevent loss of bone density, stabilize bone deterioration,stabilize bone degradation, stabilize bone degeneration, stabilize theloss of bone mass, stabilize the loss of bone density, decrease bonedeterioration, decrease bone degradation, decrease bone degeneration,decrease loss of bone mass, decrease loss of bone density, increase bonemass, increase bone density, or combinations thereof.

In embodiments of the method or use, the method or use includesadministering a compound described herein.

E. Methods of Inhibiting Estrogen Receptor

In an aspect is provided a method of inhibiting estrogen receptoractivity in a subject in need thereof, including administering to thesubject an effective amount of a compound described herein.

In an aspect is provided use of a compound as described herein in themanufacture of a medicament for inhibiting estrogen receptor activity ina subject in need of such treatment.

In an aspect is provided a compound as described herein for use ininhibiting estrogen receptor activity in a subject in need of suchtreatment. The use includes administering to the subject a compounddescribed herein. The use may include administering to the subject atherapeutically effective amount of a compound described herein.

In embodiments, the method or use includes modulation (e.g., inhibitionor reduction) of the activity of a cellular pathway (e. g., ras-MAPKcontaining pathway, PI3K/AKT containing pathway, She containing pathway,Src kinase containing pathway, JAK/STAT containing pathway, nitric oxidesynthase pathway, VEGF secretion pathway). In embodiments, the method oruse includes modulation (e.g., inhibition or reduction) of DNAsynthesis. In embodiments, the method or use includes modulation (e.g.,inhibition or reduction) of cell growth. In embodiments, the method oruse includes modulation (e.g., inhibition or reduction) of cellproliferation. In embodiments, the method or use includes modulation(e.g., inhibition or reduction) of epithelial cell proliferation. Inembodiments, the method or use includes modulation (e.g., activation orincreasing) of the degradation of ER. In embodiments, the method or useincludes modulation (e.g., activation or increasing) of theubiquitination of ER. In embodiments, the method or use includesmodulation (e.g., activation or increasing) of the degration of ER bythe proteasome. In embodiments, the method or use includes modulation(e.g., inhibition or reduction) of ER interaction with AP-1, NF-κB,MAPK, PI3K, or AKT kinase. In embodiments, the method or use includesmodulation (e.g., inhibition or reduction) of ER phosphorylation. Inembodiments, the method or use includes modulation (e.g., activation orincreasing) of tumor cell apoptosis. In embodiments, the method or useincludes modulation (e.g., activation or increasing) of cancer cellapoptosis. In embodiments, the method or use includes modulation (e.g.,activation or increasing) of ER expressing cell apoptosis. Inembodiments, the method or use includes modulation (e.g., inhibition orreduction) of ER translocation to the nucleus. In embodiments, themethod or use includes modulation (e.g., inhibition or reduction) of ERtranslocation to the cytosol.

In embodiments of the method or use, the method or use includesadministering a compound described herein.

F. Examples 1. Compound Design and Synthesis

Designed herein are new compounds based on the knowledge of how the ERantagonists, e.g., 4-hydroxy-tamoxifen, OHT, bind to the ER and preventthe downstream message to grow rapidly. The phenolic hydroxyl group ofOHT binds to the same part of the ligand binding domain (LBD) as doesthe phenolic hydroxyl group of E2 but, because of the hindered basicamino group in OHT (not present in E2), the way the protein folds aroundthe bound molecule is altered (helix 12 folds in an unusual way) and thesignal for DNA synthesis and cancer growth is inhibited. Thereforecompounds were designed which are analogues of estradiol but with anadditional large substituent at C11 of the steroid molecule. Inparticular a series of 11β-aryloxy estradiols, 1, were prepared having abasic amine positioned on the aryl ring. Molecules have been designed tobind in the LDB but not allow helix 12 to fold in an agonist mode butrather in an antagonist mode in a way similar to that of the ERantagonists.

The synthesis of the molecules began from the known ketone 3, itselfprepared in four steps from estradiol 2 (Synthesis 1). Reduction of theketone 3 with sodium borohydride gave the expected 11β-alcohol 4 due tosteric hindrance toward attack of hydride from the 3-face. Formation ofthe anion of 4 with potassium hydride in THF/DMF followed by addition of4-fluoronitrobenzene afforded the desired nitrophenyl ether 5 via afacile S_(N)Ar reaction. Reduction of the nitro group of 5 with nickelboride gave the aminophenyl ether 6. Removal of the two benzyl ethersfrom 6 by catalytic hydrogenolysis gave the first analogue, the simpleaniline 7, namely 11β-(4-amino-phenyloxy)estradiol. The analogues havinga three-atom linker between the aryl ring and the basic amine were allprepared by the same route. Thus the aniline 6 was treated withchloroacetyl chloride in the presence of DMAP to give the intermediatechloromethyl amide which was immediately reacted with any of severalsecondary amines, e.g., dimethylamine, morpholine, pyrrolidine, andpiperidine, to give the amides. Again hydrogenolysis of the benzylethers using hydrogen and a palladium catalyst gave the desiredanalogues, 8a-d (a: R₂=Me₂; b: R₂═(CH₂CH₂)₂O; c: R₂═(CH₂)₄; d:R₂═(CH₂)₅). After coupling of 6 with the acid chloride to give theamide, hydride reduction afforded the 2-(dialkylamino)ethyl amines, thebenzyl ethers of which were hydrogenolyzed to give another set ofanalogues 9a-d, namely the N-(2-aminoethyl)anilines. In addition the4-amino group was completely removed to give the simple 11β-phenyl ether10.

The availability of this bis(benzyl) aniline 6 allowed for the rapidsynthesis of several other analogues (Synthesis 2). Thus reacting3-chloropropionyl chloride with 6 followed by displacement of thechloride with the secondary amines and subsequent hydrogenolysisafforded the analogues with a 5-atom side chain ending in the basicamine, 11a-d. Likewise using 4-chlorobutanoyl chloride, afterdisplacement of the chloride with the secondary amines and subsequenthydrogenolysis, one obtained the analogues with a 6-atom side chainending in the basic amine, 12a-d. Finally following the same routestarting with 5-chloropentanoyl chloride gave the analogues with a7-atom side chain, 13a-d. Again after coupling of 6 with the 3-carbonacid chloride to give the amide, hydride reduction afforded the2-(dialkylamino)ethyl amines, the benzyl ethers of which werehydrogenolyzed to give another set of analogues 14a-d, namely theN-(3-aminopropyl)anilines. By substituting the 4-fluoronitrobenzene unitfor other aryl fluorides, one could prepare several other sets ofanalogues. Thus alkylation of the 11β-alcohol 4 with2,4-difluoronitrobenzene led to the 3-fluoro-4-nitrophenyl ether (whichafter hydrogenolysis gave the analogue 15). From that compound wereprepared the 16 analogues, 17a-d, 18a-d, 19a-d, and 20a-d and theunsubstituted aniline 16 (Synthesis 3). In a similar manner, using4-fluoro-3-trifluoro-methylnitrobenzene to alkylate the anion of 4resulted in the 3-trifluoromethyl-4-nitrophenyl ether (which afterhydrogenolysis gave the analogue 21) and thus the 16 additionalanalogues, 23a-d, 24a-d, 25a-d, and 26a-d and the unsubstituted aniline22.

Synthesis 1: Preparation of the Novel ER Antagonists 7-10.

Synthesis 2: Preparation of the Novel ER Antagonists 11-14.

Synthesis 3: Preparation of the Novel ER Antagonists 15-26.

General:

Tetrahydrofuran (THF) was distilled from benzoquinone ketyl radicalunder an argon atmosphere. Dichloromethane, toluene, benzene, andpyridine were distilled from calcium hydride under an argon atmosphere.Anhydrous N,N-dimethylformamide (DMF) was purchased from Sigma-Aldrich.All other solvents or reagents were purified according to literatureprocedures.(8S,9S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-6,7,8,9,12,13,14,15,16,17-decahydro-11H-cyclopenta[a]phenanthren-11-one(11-ketone) was prepared using literature procedures.

Instrumentation:

¹H NMR, ¹³C NMR, and ¹⁹F NMR spectra were obtained at 300 MHz, 400 MHz,or 500 MHz for proton, 75 MHz, 100 MHz, or 125 MHz for carbon, and 282MHz, or 376 MHz for fluorine are so indicated. The chemical shifts arereported in parts per million (ppm, δ). The coupling constants arereported in Hertz (Hz) and the resonance patterns are reported withnotations as the following: br (broad), s (singlet), d (double), t(triplet), q (quartet) and m (multiplet). High-resolution mass spectrawere measured on a time-of-flight LC-MS. Thin-layer chromatography (TLC)was carried out using precoated silica gel sheets. Visual detection wasperformed with ultraviolet light, p-anisaldehyde stain, potassiumpermanganate stain or iodine. Flash chromatography was performed usingsilica gel P60 (60 A, 40-63 m) with compressed air.

(8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-ol

A solution of sodium borohydride (12 wt. % in 14 M NaOH, 43.2 μL, 0.188mmol) was added gradually to a solution of the bis(benzyl-oxy)ketone(0.1459 g, 0.313 mmol) in MeOH (3.0 mL) at 0° C. The mixture was stirredat 22° C. until TLC indicated complete consumption of the startingmaterial. An aqueous saturated NH₄Cl solution was added to quench thereaction. Ethyl acetate (3×40 mL) was added to the mixture. The combinedorganic phases were washed with water and brine, and dried overanhydrous MgSO₄. Flash column chromatography on silica gel eluting with6/1 hexanes/ethyl acetate gave the target compound, the 11β-alcohol. 1HNMR (400 MHz, CDCl₃): δ 7.23-7.50 (m, 10H), 7.21 (d, J=8.5 Hz, 1H), 6.83(dd, J=8.6, 2.7 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 5.04 (s, 2H), 4.71 (m,1H), 4.61 (d, J=12.1 Hz, 1H), 4.57 (d, J=12.1 Hz, 1H), 3.49 (dd, J=8.6,7.6 Hz, 1H), 2.75-2.89 (m, 2H), 2.33-2.45 (m, 2H), 1.13 (s, 3H),0.81-2.10 (m, 10H). ¹³C NMR (100 MHz, CDCl₃): δ 157.0, 140.1, 139.2,137.2, 128.6 (2C), 128.3 (2C), 128.2, 127.9, 127.4 (2C), 127.32 (2C),127.30, 126.1, 115.7, 113.1, 88.8, 71.6, 69.9, 67.7, 50.9, 50.1, 43.9,43.1, 33.1, 30.0, 27.9, 26.7, 23.0, 14.2.

General procedure:(8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-11-(4-nitro-phenoxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene

A solution of the 11β-alcohol (0.117 g, 0.25 mmol) in anhydrous THF (2.0mL) was added gradually to the solution of potassium hydride (25 mg,0.625 mmol) in DMF (1.0 mL) at 0° C. The mixture was stirred for 10 minat 0° C. The solution of 1-fluoro-4-nitrobenzene (80 μL, 0.75 mmol) inTHF (0.5 mL) was added slowly to the reaction system. The reaction wasstirred until TLC indicated complete consumption of the startingmaterial. A saturated NH₄Cl aqueous solution was added to quench thereaction. Ethyl acetate (3×40 mL) was added to the mixture. The combinedorganic phases were washed with water and brine, and dried overanhydrous MgSO₄. Flash column chromatography on silica gel eluting with6/1 hexanes/ethyl acetate gave the target compound, the 4-nitrophenylether. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=9.3 Hz, 2H), 8.13 (d, J=9.4Hz, 1H), 7.10-7.39 (m, 8H), 6.91 (d, J=9.3 Hz, 2H), 6.84 (d, J=8.7 Hz,1H), 6.73 (d, J=2.6 Hz, 1H), 6.61 (m, 2H), 5.35 (m, 1H), 4.98 (s, 2H),4.54 (d, J=12.2 Hz, 1H), 4.44 (d, J=12.2 Hz, 1H), 3.50 (dd, J=8.1, 8.1Hz, 1H), 2.79-2.96 (m, 2H), 2.60 (d, J=10.9 Hz, 1H), 2.51 (dd, J=14.2,2.4 Hz, 1H), 1.95-2.08 (m, 2H), 0.95 (s, 3H), 0.75-1.8 (m, 7H). ¹³C NMR(100 MHz, CDCl₃): δ 163.0, 156.8, 141.2, 139.0, 138.6, 137.2, 129.1,128.5 (2C), 128.3 (2C), 128.0, 127.9, 127.4 (2C), 127.3, 126.3 (2C),126.0 (2C), 115.2 (2C), 112.6, 110.2, 88.4, 73.1, 71.6, 69.9, 50.6,48.7, 43.0, 40.3, 39.4, 33.7, 27.6, 27.3, 23.1, 13.8.

General procedure:(8S,9S,11S,13S,14S,17S)-11l-(4-aminophenoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol,JD105

Sodium borohydride (30 mg, 0.79 mmol) was added gradually to a solutionof NiCl₂.6H₂O (59 mg, 0.25 mmol) and the 11β-(4-nitrophenyl)ether (0.121g, 0.205 mmol) in MeOH (1.5 mL) and dichloromethane (3.0 mL) at 0° C.The mixture was stirred at 22° C. until TLC indicated the completeconsumption of the starting material. Diethyl ether (15 mL) and citricacid aqueous solution (5%, 10 mL) was added and stirred vigorously toquench the reaction. Diethyl ether (3×40 mL) was added to the mixture.The combined organic phases were washed with water and brine, and driedover anhydrous MgSO₄. The mixture was concentrated. The resultingresidue was dissolved in MeOH (15 mL) and added with Pd(OH)₂ (20 mg). Astream of argon was passed over the mixture and then the argon wasreplaced with hydrogen and the mixture was stirred vigorously for 1 h.The mixture was filtered through a thick pad of Celite and the organicphase was evaporated. The residue was purified via flash columnchromatography on silica gel eluting with 6/1 hexanes/ethyl acetate gavethe target compound, the 4-aminophenyl ether diol. ¹H NMR (500 MHz,CDCl₃) δ 6.99 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4Hz, 2H), 6.58 (s, 1H), 6.53 (d, J=7.9 Hz, 1H), 5.16 (m, 1H), 3.74 (m,1H), 1.00 (s, 3H), 0.69-3.0 (m, 17H). ¹³C NMR (125 MHz, CDCl₃): δ 153.3,150.9, 139.4, 138.7, 128.5, 126.8, 116.8 (2C), 116.6 (2C), 115.5, 113.0,82.4, 72.2, 50.8, 49.0, 43.0, 38.3, 34.0, 30.5, 29.6, 27.4, 23.1, 12.9.

General procedure:N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-(dimethyl-amino)acetamide

Sodium borohydride (30 mg, 0.79 mmol) was added gradually to a solutionof NiCl₂.6H₂O (59 mg, 0.25 mmol) and 11β-(4-nitrophenyl)ether (0.121 g,0.205 mmol) in MeOH (1.5 mL) and dichloromethane (3.0 mL) at 0° C. Themixture was stirred at 22° C. until TLC indicated the completeconsumption of the starting material. Diethyl ether (15 mL) and citricacid aqueous solution (5%, 10 mL) was added and stirred vigorously toquench the reaction. Diethyl ether (3×40 mL) was added to the mixture.The combined organic phases were washed with water and brine, dried overanhydrous MgSO₄. The mixture was concentrated. The resulting residue wasdissolved in dichloromethane (2.0 mL) and DMAP (cat.) and Et₃N (0.82mmol) were added. Chloroacetyl chloride (0.65 mmol) was added graduallyto the mixture at 0° C. and the reaction mixture was stirred at 22° C.for 2 h. Ethyl acetate (3×40 mL) was added to the mixture. The combinedorganic phases were washed with water and brine, and dried overanhydrous MgSO₄. The organic phase was concentrated. The resultingresidue was dissolved in dimethylformamide (2.0 mL) and dimethylamine(1.0 mmol) was added to the reaction system at 22° C. The reaction wasstirred until TLC indicated the complete consumption of the startingmaterial. Ethyl acetate (3×40 mL) was added to the mixture. The combinedorganic phases were washed with water and brine, dried over anhydrousMgSO₄ and the organic phase was evaporated. The residue was purified viaflash column chromatography on silica gel eluting with 2/1 hexanes/ethylacetate gave the targeted compounds. ¹H NMR (300 MHz, CDCl₃): δ 9.00 (s,1H), 7.12-7.53 (m, 12H), 6.95 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.9 Hz, 2H),6.68 (d, J=2.6 Hz, 1H), 6.65 (dd, J=8.4, 2.4 Hz, 1H), 5.20 (m, 1H), 4.98(s, 2H), 4.51 (d, J=12.3 Hz, 1H), 4.47 (d, J=12.3 Hz, 1H), 3.47 (m, 2H),2.38 (s, 6H), 1.01 (s, 3H), 0.80-3.11 (m, 14H). ¹³C NMR (75 MHz, CDCl₃):δ 168.4, 156.6, 154.5, 139.1, 138.5, 137.4, 130.5, 128.8, 128.5 (2C),128.3 (2C), 127.8, 127.5 (2C), 127.4 (2C), 127.35, 126.6, 121.3 (2C),115.8 (2C), 115.0, 112.6, 88.6, 71.9, 71.6, 69.9, 63.6, 51.0, 48.9, 46.0(2C), 43.2, 39.4, 33.7, 29.7, 27.8, 27.5, 23.1, 13.7. HR-MS (ESI) calcdfor [C₄₂H₄₈N₂O₄ H]⁺ 645.3693, found 645.3707.

General procedure:N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-(dimethyl-amino)acetamide,JD104

To a solution of the dibenzyl amide (0.065 g, 0.1 mmol) in MeOH (5.0 mL)was added Pd(OH)₂ (10 mg). Argon was passed over the mixture and thenthe argon was replaced with hydrogen and the mixture was stirredvigorously for 1 h. The mixture was filtered through a thick pad ofCelite and the organic phase was evaporated. The residue was purifiedvia flash column chromatography on silica gel eluting with 15/1dichloro-methane/MeOH to give the target compound, the amide diol. ¹HNMR (400 MHz, MeOD): δ 7.41 (d, J=9.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 1H),6.86 (d, J=9.7 Hz, 2H), 6.48 (d, J=2.7 Hz, 1H), 6.40 (dd, J=8.7, 2.7 Hz,1H), 5.31 (m, 1H), 3.60-3.69 (m, 1H), 3.33 (s, 2H), 2.40 (br s, 6H),0.88 (s, 3H), 0.80-3.38 (m, 13H). ¹³C NMR (100 MHz, MeOD): δ 169.4,156.3, 154.8, 138.6, 130.6, 127.7, 126.8, 122.4 (2C), 115.4 (2C), 115.1,112.9, 81.9, 72.3, 62.8, 50.8, 49.2, 44.8, 43.2 (2C), 38.4, 34.6, 29.8,29.5, 27.6, 23.0, 12.7. HR-MS (ESI) calcd for [C₂₈H₃₇N₂O₄ H]⁺ 465.2753,found 465.2759.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-morpholinoacetamide

¹H NMR (400 MHz, CDCl₃): δ 8.91 (s, 1H), 7.18-7.49 (m, 12H), 6.96 (d,J=8.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 2H), 6.71 (d, J=2.6 Hz, 1H), 6.65 (dd,J=8.6, 2.6 Hz, 1H), 5.22 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=12.0 Hz, 1H),4.47 (d, J=12.0 Hz, 1H), 4.09 (m, 1H), 3.70-3.82 (m, 2H), 3.40-3.52 (m,1H), 1.01 (s, 3H), 0.80-3.20 (m, 20H). ¹³C NMR (100 MHz, CDCl₃): δ167.6, 156.6, 154.6, 139.1, 138.5, 137.3, 130.2, 128.8, 128.5 (2C),128.3 (2C), 127.8, 127.5 (2C), 127.4, 127.3 (2C), 126.5, 121.4 (2C),115.8 (2C), 114.9, 112.6, 88.5, 71.9, 71.5, 69.9, 67.1 (2C), 62.4, 53.8(2C), 50.9, 48.9, 43.1, 39.3, 33.7, 29.8, 27.7, 23.1, 19.1, 13.7.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-morpholinoacetamide,JD103

¹H NMR (400 MHz, MeOD): δ 7.41 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.0 Hz,1H), 6.85 (d, J=9.0 Hz, 2H), 6.48 (d, J=2.3 Hz, 1H), 6.40 (dd, J=8.5,2.7 Hz, 1H), 5.30 (m, 1H), 3.75 (t, J=4.0 Hz, 4H), 3.13 (s, 2H), 2.57(t, J=4.0 Hz, 4H), 0.88 (s, 3H), 0.8-3.3 (m, 14H). ¹³C NMR (100 MHz,MeOD): δ 169.1, 154.9, 154.4, 138.2, 130.1, 127.3, 126.3, 122.0 (2C),115.1 (2C), 114.8, 112.5, 81.5, 71.9, 66.4 (2C), 61.8, 53.4 (2C), 50.4,48.7, 42.8, 38.0, 34.2, 29.4, 29.1, 27.2, 22.6, 12.3. HR-MS (ESI) calcdfor [C₃₀H₃₈N₂O₅ H]⁺ 507.2859, found 507.2843.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-(pyrrolidin-1-yl)acetamide

¹H NMR (300 MHz, CDCl₃): δ 8.99 (s, 1H), 7.20-7.51 (m, 12H), 6.95 (d,J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.71 (d, J=2.8 Hz, 1H), 6.65 (dd,J=8.9, 3.0 Hz, 1H), 5.20 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=11.7 Hz, 1H),4.47 (d, J=11.7 Hz, 1H), 3.47 (s, 2H), 2.70 (m, 4H), 1.86 (m, 4H), 1.05(s, 3H), 0.80-3.56 (m, 14H). ¹³C NMR (75 MHz, CDCl₃): δ 168.8, 156.6,154.5, 139.1, 138.5, 137.4, 130.5, 128.8, 128.5 (2C), 128.3 (2C), 127.8,127.5 (2C), 127.4 (2C), 127.3, 126.6, 121.4 (2C), 115.8 (2C), 115.0,112.5, 88.5, 71.9, 71.6, 69.9, 59.7, 54.6 (2C), 51.0, 48.9, 43.1, 39.4,33.7, 29.8, 27.8, 27.5, 24.1 (2C), 23.1, 13.7.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-(pyrrolidin-1-yl)acetamide,JD102

¹H NMR (400 MHz, MeOD): δ 7.40 (d, J=8.9 Hz, 2H), 6.88 (d, J=8.0 Hz,1H), 6.85 (d, J=8.9 Hz, 2H), 6.48 (d, J=2.7 Hz, 1H), 6.40 (dd, J=8.0,2.4 Hz, 1H), 5.32 (m, 1H), 3.65 (m, 1H), 3.40 (s, 2H), 2.78 (m, 4H),1.88 (m, 4H), 0.88 (s, 3H), 0.80-2.60 (m, 13H). ¹³C NMR (100 MHz, MeOD):δ 170.1, 156.3, 155.8, 139.6, 131.6, 128.7, 123.4 (2C), 123.3, 116.5(2C), 116.2, 113.9, 79.3, 73.3, 55.4 (2C), 51.8, 50.2, 49.5, 44.2, 39.4,35.6, 30.8, 30.5, 28.6, 24.6 (2C), 24.0, 13.8. MS (ESI) m/z (%) 491([M+1]⁺, 100), 447 (15), 155 (28). HR-MS (ESI) calcd for [C₂₀H₂₂O₅ H]⁺491.2910, found 491.2926.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-(piperidin-1-yl)acetamide

¹H NMR (300 MHz, CDCl₃): δ 9.05 (s, 1H), 7.10-7.55 (m, 12H), 6.95 (d,J=8.4 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.66 (d,J=8.4 Hz, 1H), 5.22 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=12.3 Hz, 1H), 4.47(d, J=12.3 Hz, 1H), 2.72 (m, 4H), 1.86 (m, 4H), 1.01 (s, 3H), 0.70-3.60(m, 18H). ¹³C NMR (75 MHz, CDCl₃): δ 168.5, 156.7, 154.4, 139.0, 138.4,137.3, 130.5, 128.7, 128.5 (2C), 128.2 (2C), 127.8, 127.4 (2C), 127.3(2C), 127.27, 126.5, 121.4 (2C), 115.7 (2C), 114.9, 112.5, 88.5, 71.8,71.5, 69.8, 59.6, 54.5 (2C), 51.0, 48.8, 43.1, 39.3, 38.5, 33.7, 29.7,29.6, 27.7, 24.0 (2C), 23.0, 14.1.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-2-(piperidin-1-yl)acetamide,JD101

¹H NMR (400 MHz, MeOD): δ 7.40 (d, J=8.9 Hz, 2H), 6.88 (d, J=8.4 Hz,1H), 6.85 (d, J=8.9 Hz, 2H), 6.47 (d, J=2.6 Hz, 1H), 6.39 (dd, J=8.4,2.6 Hz, 1H), 5.31 (m, 1H), 3.43 (s, 2H), 2.81 (m, 4H), 1.89 (m, 4H),0.88 (s, 3H), 0.75-3.7 (m, 16H). ¹³C NMR (100 MHz, MeOD): δ 169.9,156.3, 155.8, 139.6, 131.6, 128.7, 127.7, 123.4 (2C), 116.4 (2C), 116.1,113.9, 82.9, 73.3, 61.5, 59.9, 55.4, 51.8, 50.2, 44.2 (2C), 39.4, 35.6,30.8, 30.5, 28.6, 24.6 (2C), 24.0, 13.7. HR-MS (ESI) calcd for[C₃₁H₄₀N₂O₄ H]⁺ 491.2910, found 491.2892.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-morpholinopropanamide

¹H NMR (300 MHz, CDCl₃): δ 10.5 (s, 1H), 7.20-7.50 (m, 12H), 6.96 (d,J=8.4 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.65 (dd,J=7.7, 2.4 Hz, 1H), 5.20 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=12.0 Hz, 1H),4.47 (d, J=12.0 Hz, 1H), 3.82 (t, J=4.2 Hz, 4H), 2.61 (t, J=4.2 Hz, 4H),1.01 (s, 3H), 0.72-3.78 (m, 18H). ¹³C NMR (75 MHz, CDCl₃): δ 169.9,156.6, 154.1, 139.1, 138.5, 137.3, 131.3, 128.8, 128.5 (2C), 128.2 (2C),127.8, 127.4 (2C), 127.32, 127.30 (2C), 126.5, 121.2 (2C), 115.8 (2C),114.9, 112.5, 88.5, 71.9, 71.4, 69.9, 67.0 (2C), 54.3, 52.8 (2C), 50.9,48.9, 43.1, 39.3, 33.7, 32.1, 29.7, 27.7, 27.4, 23.0, 13.7.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-morpholinopropanamide,JD106

¹H NMR (300 MHz, MeOD): δ 7.38 (d, J=9.0 Hz, 2H), 6.89 (d, J=8.4 Hz,1H), 6.85 (d, J=9.0 Hz, 2H), 6.48 (d, J=2.7 Hz, 1H), 6.40 (dd, J=8.4,2.4 Hz, 1H), 5.32 (m, 1H), 3.71 (t, J=4.5 Hz, 4H), 2.54 (t, J=4.5 Hz,4H), 0.89 (s, 3H), 0.80-3.69 (m, 18H). ¹³C NMR (75 MHz, MeOD): δ 172.5,156.1, 155.8, 139.6, 132.2, 128.7, 127.7, 123.2 (2C), 116.5 (2C), 116.2,113.9, 82.9, 73.3, 67.7 (2C), 55.6, 54.4 (2C), 51.8, 50.2, 44.2, 39.4,35.6, 34.4, 30.8, 30.5, 28.6, 24.0, 13.7. HR-MS (ESI) calcd for[C₃₁H₄₀N₂O₅ H]⁺ 521.3016, found 521.3010.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-(piperidin-1-yl)propan-amide

¹H NMR (300 MHz, CDCl₃): δ 10.75 (s, 1H), 7.20-7.55 (m, 12H), 6.96 (d,J=8.4 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.66 (dd,J=8.3, 2.4 Hz, 1H), 5.21 (m, 1H), 4.98 (s, 2H), 4.50 (d, J=11.6 Hz, 1H),4.48 (d, J=11.6 Hz, 1H), 2.60 (m, 4H), 1.72 (m, 4H), 1.01 (s, 3H),0.70-3.75 (m, 20H). ¹³C NMR (75 MHz, CDCl₃): δ 169.9, 156.6, 154.0,139.1, 138.4, 137.3, 131.6, 128.8, 128.5 (2C), 128.2 (2C), 127.8, 127.4(2C), 127.31 (2C), 127.27, 126.5, 121.1 (2C), 115.8 (2C), 114.9, 112.5,88.5, 71.8, 71.5, 69.9, 54.3, 53.6 (2C), 51.0, 48.9, 43.1, 39.3, 33.7,32.4, 29.7, 27.7, 27.5, 25.5 (2C), 23.8, 23.0, 13.7. HR-MS (ESI) calcdfor [C₄₆H₅₄N₂O₄ H]⁺ 699.4162, found 699.4180.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-(piperidin-1-yl)propanamide,JD107

¹H NMR (400 MHz, MeOD): δ 7.41 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.2 Hz,1H), 6.85 (d, J=8.8 Hz, 2H), 6.48 (d, J=2.6 Hz, 1H), 6.40 (dd, J=8.2,2.6 Hz, 1H), 5.31 (m, 1H), 2.87 (m, 4H), 1.84 (m, 4H), 0.87 (s, 3H),0.79-3.75 (m, 20H). ¹³C NMR (100 MHz, MeOD): δ 169.7, 156.2, 155.8,139.6, 132.0, 128.7, 127.8, 123.2 (2C), 116.5 (2C), 116.2, 113.9, 82.8,73.3, 54.6, 54.3, 51.8, 50.1, 44.2 (2C), 39.4, 35.6, 31.4, 30.9, 30.5,28.6, 24.4 (2C), 24.0, 22.8, 13.8.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-(pyrrolidin-1-yl)propan-amide

¹H NMR (300 MHz, CDCl₃): δ 10.50 (s, 1H), 7.20-7.49 (m, 12H), 6.96 (d,J=8.7 Hz, 1H), 6.84 (d, J=9.0 Hz, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.66 (dd,J=8.6, 2.6 Hz, 1H), 5.20 (m, 1H), 4.98 (s, 2H), 4.50 (d, J=12.6 Hz, 1H),4.48 (d, J=12.6 Hz, 1H), 2.85 (m, 4H), 1.92 (m, 4H), 1.00 (s, 3H),0.82-3.55 (m, 18H). ¹³C NMR (75 MHz, CDCl₃): δ 169.4, 156.5, 154.1,139.1, 138.4, 137.3, 131.3, 128.8, 128.4 (2C), 128.2 (2C), 127.7, 127.4(2C), 127.3 (2C), 127.2, 126.5, 121.4 (2C), 115.7 (2C), 112.5, 112.5,88.5, 71.8, 71.5, 69.8, 53.4 (2C), 51.5, 50.9, 48.8, 43.0, 39.2, 34.1,33.6, 29.7, 27.7, 27.4, 23.5 (2C), 23.0, 13.6. HR-MS (ESI) calcd for[C₄₅H₅₂N₂O₄ H]⁺ 685.4005, found 685.4021.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-(pyrrolidin-1-yl)propanamide,JD108

¹H NMR (400 MHz, MeOD): δ 7.40 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.1 Hz,1H), 6.84 (d, J=8.7 Hz, 2H), 6.50 (d, J=2.6 Hz, 1H), 6.42 (dd, J=8.1,2.6 Hz, 1H), 5.27 (m, 1H), 2.87 (m, 4H), 1.27 (m, 4H), 0.88 (s, 3H),0.80-3.74 (m, 18H). ¹³C NMR (75 MHz, MeOD): δ 169.0, 155.8, 155.3,139.4, 131.5, 128.4, 127.4, 122.8 (2C), 116.3 (2C), 116.0, 113.7, 82.5,73.0, 55.1 (2C), 52.1, 51.5, 43.9, 39.1, 35.2, 32.4, 30.5, 30.4, 30.3,28.3, 23.8 (2C), 23.7, 13.6. HR-MS (ESI) calcd for [C₃₁H₄₀N₂O₄ H]⁺505.3066, found 505.3045.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-(dimethylamino)propan-amide

¹H NMR (300 MHz, CDCl₃): δ 8.01 (s, 1H), 7.19-7.55 (m, 12H), 6.95 (d,J=8.4 Hz, 1H), 6.84 (d, J=8.9 Hz, 2H), 6.65 (d, J=2.6 Hz, 1H), 6.62 (dd,J=8.4, 2.4 Hz, 1H), 5.18 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=11.3 Hz, 1H),4.48 (d, J=11.3 Hz, 1H), 2.52 (s, 6H), 1.02 (s, 3H), 0.80-3.80 (m, 18H).¹³C NMR (75 MHz, CDCl₃): δ 166.2, 156.5, 154.5, 139.0, 138.4, 137.2,130.7, 128.7, 128.4 (2C), 128.2 (2C), 127.7, 127.3 (2C), 127.2 (2C),126.8, 126.4, 121.7 (2C), 115.6 (2C), 114.9, 112.4, 88.4, 72.0, 71.4,69.7, 50.8, 48.8, 45.8, 43.0 (2C), 39.2, 33.6, 29.7, 29.6, 27.6, 27.3,23.0, 20.5, 13.6.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-3-(dimethylamino)propanamide,JD109

¹H NMR (300 MHz, MeOD): δ 7.38 (d, J=9.0 Hz, 2H), 6.89 (d, J=8.4 Hz,1H), 6.84 (d, J=9.0 Hz, 2H), 6.48 (d, J=2.7 Hz, 1H), 6.41 (dd, J=8.4,2.7 Hz, 1H), 5.28 (m, 1H), 2.14 (s, 6H), 0.88 (s, 3H), 0.80-3.70 (m,18H). ¹³C NMR (75 MHz, MeOD): δ 175.1, 156.0, 155.8, 139.5, 132.4,128.7, 127.7, 123.3 (2C), 116.4 (2C), 116.2, 113.9, 82.9, 73.3, 51.8,50.1, 44.2 (2C), 39.4, 35.6, 30.8, 30.7, 30.5, 28.6, 24.0, 13.7, 10.4.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-morpholinobutanamide

¹H NMR (300 MHz, CDCl₃): δ 8.15 (s, 1H), 7.20-7.50 (m, 12H), 6.97 (d,J=8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 6.71 (d, J=2.5 Hz, 1H), 6.67 (dd,J=8.4, 2.6 Hz, 1H), 5.19 (m, 1H), 4.99 (s, 2H), 4.52 (d, J=12.9 Hz, 1H),4.49 (d, J=12.9 Hz, 1H), 3.75 (t, J=4.3 Hz, 4H), 2.53 (t, J=4.3 Hz, 4H),1.03 (s, 3H), 0.9-3.8 (m, 20H). ¹³C NMR (75 MHz, CDCl₃): δ 170.8, 156.5,154.3, 139.0, 138.4, 137.2, 130.8, 128.7, 128.4 (2C), 128.2 (2C), 127.7,127.3 (2C), 127.26, 127.22 (2C), 126.4, 121.6 (2C), 115.7 (2C), 114.8,112.4, 88.4, 71.8, 71.4, 69.7, 66.7 (2C), 57.4, 53.3 (2C), 50.8, 48.8,43.0, 39.2, 35.1, 33.6, 29.7, 27.6, 27.3, 23.0, 21.7, 13.6. HR-MS (ESI)calcd for [C₄₆H₅₄N₂O₅ H]⁺ 715.4111, found 715.4106.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-morpholinobutanamide,JD110

¹H NMR (300 MHz, MeOD): δ 7.40 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.7 Hz,1H), 6.85 (d, J=9.0 Hz, 2H), 6.49 (d, J=2.4 Hz, 1H), 6.41 (dd, J=8.1,2.4 Hz, 1H), 5.28 (m, 1H), 3.82 (m, 4H), 2.49 (m, 4H), 0.88 (s, 3H),0.80-3.70 (m, 20H). ¹³C NMR (75 MHz, MeOD): δ 173.0, 156.1, 155.8,139.6, 132.1, 128.7, 127.8, 123.4 (2C), 116.5 (2C), 116.2, 113.9, 82.8,73.3, 66.0 (2C), 58.6, 53.7 (2C), 51.8, 50.0, 44.2, 39.3, 35.6, 34.8,30.8, 30.5, 28.6, 24.0, 21.6, 13.8.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-(pyrrolidin-1-yl)butan-amide

¹H NMR (300 MHz, MeOD): δ 7.19-7.42 (m, 12H), 6.95 (d, J=8.8 Hz, 1H),6.82 (d, J=9.0 Hz, 2H), 6.66 (d, J=2.7 Hz, 1H), 6.56 (dd, J=8.7, 2.8 Hz,1H), 5.26 (m, 1H), 4.93 (s, 2H), 4.46 (d, J=11.4 Hz, 1H), 4.42 (d,J=11.4 Hz, 1H), 2.50 (m, 4H), 2.05 (m, 4H), 0.94 (s, 3H), 0.82-3.60 (m,20H). ¹³C NMR (75 MHz, MeOD): δ 172.4, 157.9, 156.0, 140.4, 139.7,139.0, 132.2, 130.2, 129.4, 129.3 (2C), 128.7 (2C), 128.6, 128.5 (2C),128.46 (2C), 127.8, 123.4 (2C), 116.5 (2C), 115.8, 113.6, 90.2, 73.3,72.8, 70.8, 55.9, 55.1 (2C), 54.8, 51.8, 50.0, 44.3, 40.2, 35.2, 34.2,30.9, 28.7, 28.5, 24.0 (2C), 23.0, 14.4.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-(pyrrolidin-1-yl)butanamide,JD111

¹H NMR (300 MHz, MeOD): δ 7.38 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.1 Hz,1H), 6.85 (d, J=9.0 Hz, 2H), 6.48 (d, J=2.4 Hz, 1H), 6.40 (dd, J=8.7,2.7 Hz, 1H), 5.33 (m, 1H), 3.00 (m, 4H), 1.95 (m, 4H), 0.89 (s, 3H),0.79-3.80 (m, 20H). 13C NMR (75 MHz, MeOD): δ 172.7, 156.5, 156.3,139.4, 132.5, 128.7, 128.0, 123.3 (2C), 116.5 (2C), 116.3, 114.0, 82.9,73.3, 56.6, 54.9 (2C), 51.6, 50.1, 44.1, 39.3, 35.7, 34.9, 30.8, 30.6,28.4, 24.3, 24.2 (2C), 24.1, 13.4.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-(piperidin-1-yl)butanamide

¹H NMR (300 MHz, CDCl₃): δ 9.52 (s, 1H), 7.56 (d, J=8.7 Hz, 2H),7.18-7.48 (m, 10H), 6.95 (d, J=8.7 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 6.70(d, J=2.4 Hz, 1H), 6.65 (dd, J=8.4, 2.4 Hz, 1H), 5.18 (m, 1H), 4.97 (s,2H), 4.49 (d, J=12.3 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 2.90 (m, 4H),1.60 (m, 4H), 0.99 (s, 3H), 0.80-3.78 (m, 22H). ¹³C NMR (75 MHz, CDCl₃):δ 169.8, 156.5, 154.2, 139.1, 138.4, 137.3, 131.2, 128.8, 128.4 (2C),128.2 (2C), 127.7, 127.4 (2C), 127.3 (2C), 127.2, 126.5, 121.6 (2C),115.6 (2C), 114.9, 112.5, 88.4, 71.7, 71.4, 69.8, 60.6, 56.5, 53.5 (2C),50.9, 48.8, 43.0, 39.2, 33.6, 31.4, 29.6 (2C), 27.7, 27.4, 23.0, 22.7,20.3, 13.6. HR-MS (ESI) calcd for [C₄₇H₅₆N₂O₄ H]⁺ 713.4318, found713.4321.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-(piperidin-1-yl)butanamide,JD112

¹H NMR (300 MHz, MeOD): δ 7.38 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz,1H), 6.84 (d, J=9.0 Hz, 2H), 6.48 (d, J=2.4 Hz, 1H), 6.40 (dd, J=8.4,2.7 Hz, 1H), 5.29 (m, 1H), 2.50 (m, 4H), 1.65 (m, 4H), 0.88 (s, 3H),0.80-3.71 (m, 22H). 13C NMR (75 MHz, MeOD): δ 173.5, 156.0, 155.8,139.5, 132.2, 128.7, 127.7, 123.3 (2C), 116.4 (2C), 116.2, 113.9, 82.8,73.3, 59.4, 55.2 (2C), 51.8, 50.1, 44.2, 39.3, 35.6, 35.5, 30.8, 30.5,28.6, 26.1 (2C), 24.8, 24.0, 23.1, 13.7. HR-MS (ESI) calcd for[C₃₃H₄₄N₂O₄ H]⁺ 533.3380, found 533.3358.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-(dimethylamino)butan-amide

¹H NMR (300 MHz, CDCl₃): δ 9.50 (s, 1H), 7.15-7.70 (m, 12H), 6.97 (d,J=8.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 6.71 (d, J=2.6 Hz, 1H), 6.68 (dd,J=8.4, 2.4 Hz, 1H), 5.21 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=11.4 Hz, 1H),4.49 (d, J=11.4 Hz, 1H), 2.41 (s, 6H), 1.02 (s, 3H), 0.79-3.80 (m, 20H).¹³C NMR (75 MHz, CDCl₃): δ 171.1, 156.5, 154.0, 139.0, 138.4, 137.2,131.5, 128.7, 128.4 (2C), 128.2 (2C), 127.7, 127.4 (2C), 127.3 (2C),127.2, 126.5, 121.2 (2C), 115.7 (2C), 114.9, 112.4, 88.4, 71.8, 71.4,69.8, 58.9, 50.8, 48.8, 45.0 (2C), 43.0, 39.2, 36.5, 33.6, 29.7, 27.6,27.4, 23.0, 22.8, 13.6. HR-MS (ESI) calcd for [C₄₄H₅₂N₂O₄ H]⁺ 673.4005,found 673.4008.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-4-(dimethylamino)butanamide,JD116

¹H NMR (300 MHz, MeOD): δ 7.42 (d, J=9.0 Hz, 2H), 6.88 (d, J=8.7 Hz,1H), 6.84 (d, J=9.0 Hz, 2H), 6.49 (d, J=2.1 Hz, 1H), 6.42 (dd, J=8.6,2.6 Hz, 1H), 5.29 (m, 1H), 2.90 (s, 6H), 0.87 (s, 3H), 0.80-3.70 (m,20H). ¹³C NMR (75 MHz, MeOD): δ 172.4, 156.0, 155.7, 139.5, 132.0,128.7, 127.7, 123.4 (2C), 116.4 (2C), 116.2, 113.9, 82.8, 73.3, 58.7,51.7, 50.0, 44.1, 43.7 (2C), 39.3, 35.5, 34.2 30.8, 30.4, 28.5, 23.9,21.6, 13.8. HR-MS (ESI) calcd for [C₃₀H₄₀N₂O₄ H]⁺ 493.3066, found493.3063.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-morpholinopentanamide

¹H NMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 7.20-7.48 (m, 12H), 6.96 (d,J=8.4 Hz, 1H), 6.84 (d, J=9.0 Hz, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.65 (dd,J=8.4, 2.4 Hz, 1H), 5.21 (m, 1H), 4.98 (s, 2H), 4.51 (d, J=12.8 Hz, 1H),4.48 (d, J=12.8 Hz, 1H), 3.72 (t, J=4.2 Hz, 4H), 2.48 (t J=4.2 Hz, 4H),1.01 (s, 3H), 0.80-3.70 (m, 22H). ¹³C NMR (75 MHz, CDCl₃): δ 170.9,156.5, 154.4, 139.0, 138.4, 137.2, 130.6, 128.7, 128.4 (2C), 128.2 (2C),127.7, 127.4 (2C), 127.3 (2C), 127.2, 126.4, 121.8 (2C), 115.7 (2C),114.9, 112.5, 88.4, 71.8, 71.4, 69.8, 66.7 (2C), 58.4, 53.5 (2C), 50.8,48.8, 43.0, 39.2, 37.1, 33.6, 29.7, 27.6, 27.4, 25.8, 23.4, 23.0, 13.6.HR-MS (ESI) calcd for [C₄₇H₅₆N₂O₅ H]⁺ 729.4268, found 729.4296.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-morpholinopentanamide,JD113

¹H NMR (300 MHz, MeOD): δ 7.39 (d, J=9.0 Hz, 2H), 6.89 (d, J=8.7 Hz,1H), 6.84 (d, J=9.0 Hz, 2H), 6.48 (d, J=2.7 Hz, 1H), 6.41 (dd, J=8.4,2.4 Hz, 1H), 5.29 (m, 1H), 3.76 (d, J=4.2 Hz, 4H), 2.78 (t, J=4.2 Hz,4H), 0.88 (s, 3H), 0.80-3.70 (m, 22H). ¹³C NMR (75 MHz, MeOD): δ 173.7,156.0, 155.8, 139.6, 132.3, 128.7, 127.8, 123.3 (2C), 116.4 (2C), 116.2,113.9, 82.8, 73.3, 66.5 (2C), 59.1, 54.1 (2C), 51.8, 50.1, 44.2, 39.3,37.1, 35.6, 30.8, 30.5, 28.6, 25.7, 24.3, 24.0, 13.8.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-(pyrrolidin-1-yl)pentan-amide

¹H NMR (300 MHz, CDCl₃): δ 9.27 (s, 1H), 7.19-7.72 (m, 12H), 6.96 (d,J=8.4 Hz, 1H), 6.81 (m, 2H), 6.69 (s, 1H), 6.64 (d, J=8.4 Hz, 1H), 5.20(m, 1H), 4.95 (s, 2H), 4.49 (d, J=11.6 Hz, 1H), 4.46 (d, J=11.6 Hz, 1H),2.80 (m, 4H), 1.78 (m, 4H), 0.99 (s, 3H), 0.80-3.60 (m, 22H). ¹³C NMR(75 MHz, CDCl₃): δ 171.3, 156.5, 153.9, 139.0, 138.4, 137.2, 131.6,128.8, 128.4 (2C), 128.2 (2C), 127.7, 127.4 (2C), 127.3 (2C), 127.2,126.5, 121.7 (2C), 115.5 (2C), 114.8, 112.4, 88.4, 71.6, 71.4, 69.7,54.8, 53.3 (2C), 50.8, 48.7, 45.5, 43.0, 39.1, 36.5, 33.6, 29.71, 29.68,27.6, 27.3, 26.0, 23.0 (2C), 13.7.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-(pyrrolidin-1-yl)pentanamide,JD114

¹H NMR (300 MHz, MeOD): δ 7.42 (d, J=8.1 Hz, 2H), 6.90 (m, 1H), 6.89 (d,J=8.1 Hz, 2H), 6.48 (s, 1H), 6.42 (d, J=6.5 Hz, 1H), 5.30 (m, 1H), 2.49(m, 4H), 1.71 (m, 4H), 0.88 (s, 3H), 0.80-3.70 (m, 22H). ¹³C NMR (75MHz, MeOD): δ 173.5, 156.0, 155.8, 139.6, 132.3, 128.7, 127.7, 123.3(2C), 116.5 (2C), 116.2, 113.9, 82.8, 73.3, 55.9 (2C), 55.0, 51.8, 50.1,44.2, 39.4, 36.7, 35.6, 30.8, 30.7, 30.5, 28.6, 26.5, 24.0 (2C), 23.7,13.8.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-(piperidin-1-yl)pentan-amide

¹H NMR (300 MHz, CDCl₃): δ 8.55 (s, 1H), 7.51 (d, J=8.7 Hz, 2H),7.20-7.46 (m, 10H), 6.96 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.7 Hz, 2H), 6.69(d, J=2.3 Hz, 1H), 6.65 (dd, J=8.3, 2.5 Hz, 1H), 5.20 (m, 1H), 4.97 (s,2H), 4.49 (d, J=11.4 Hz, 1H), 4.46 (d, J=11.4 Hz, 1H), 2.58 (m, 4H),1.71 (m, 4H), 1.00 (s, 3H), 0.80-3.55 (m, 24H). ¹³C NMR (75 MHz, CDCl₃):δ 171.1, 156.5, 154.2, 139.0, 138.4, 137.2, 131.2, 128.7, 128.4 (2C),128.2 (2C), 127.7, 127.4 (2C), 127.3 (2C), 127.2, 126.5, 121.8 (2C),115.6 (2C), 114.8, 112.4, 88.4, 71.8, 71.4, 69.8, 57.6, 53.8 (2C), 50.8,48.8, 43.0, 39.2, 36.5, 33.6, 29.7, 27.6, 27.3, 24.6, 24.1 (2C), 23.2,23.1, 23.0, 14.1.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-(piperidin-1-yl)pentanamide,JD115

¹H NMR (300 MHz, MeOD): δ 7.42 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz,1H), 6.85 (d, J=8.7 Hz, 2H), 6.49 (d, J=2.1 Hz, 1H), 6.42 (dd, J=8.4,2.7 Hz, 1H), 5.30 (m, 1H), 2.42 (m, 4H), 1.75 (m, 4H), 0.88 (s, 3H),0.80-3.70 (m, 24H). 13C NMR (75 MHz, MeOD): δ 173.4, 156.0, 155.8,139.6, 132.2, 128.7, 127.8, 123.3 (2C), 116.5 (2C), 116.2, 113.9, 82.8,73.3, 57.9, 54.3 (2C), 51.8, 50.1, 44.2, 39.3, 36.7, 35.6, 30.8, 30.5,28.6, 24.5, 24.2 (2C), 24.0, 23.7, 22.7, 13.8.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-(dimethylamino)pentan-amide

¹H NMR (300 MHz, CDCl₃): δ 8.04 (s, 1H), 7.18-7.46 (m, 12H), 6.96 (d,J=8.4 Hz, 1H), 6.83 (d, J=8.7 Hz, 2H), 6.70 (d, J=2.3 Hz, 1H), 6.66 (dd,J=8.3, 2.8 Hz, 1H), 5.20 (m, 1H), 4.97 (s, 2H), 4.50 (d, J=11.6 Hz, 1H),4.47 (d, J=11.6 Hz, 1H), 2.30 (s, 6H), 1.00 (s, 3H), 0.80-3.60 (m, 22H).¹³C NMR (75 MHz, CDCl₃): δ 171.1, 156.5, 154.2, 139.0, 138.4, 137.2,130.9, 128.7, 128.4 (2C), 128.1 (2C), 127.7, 127.3 (2C), 127.2 (2C),127.15, 126.4, 121.7 (2C), 115.6 (2C), 114.8, 112.4, 88.4, 71.8, 71.4,69.7, 58.8, 50.8, 48.8, 45.3 (2C), 43.0, 39.2, 36.9, 33.6, 31.8, 29.7,27.6, 26.5, 23.4, 21.5, 13.8.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)phenyl)-5-(dimethylamino)pentanamide,JD117

¹H NMR (300 MHz, MeOD): δ 7.39 (d, J=9.0 Hz, 2H), 6.89 (d, J=8.4 Hz,1H), 6.85 (d, J=8.7 Hz, 2H), 6.48 (d, J=2.1 Hz, 1H), 6.41 (dd, J=8.3,2.7 Hz, 1H), 5.29 (m, 1H), 2.50 (s, 6H), 0.88 (s, 3H), 0.80-3.70 (m,22H). ¹³C NMR (75 MHz, MeOD): δ 173.7, 156.0, 155.8, 139.6, 132.3,128.7, 127.7, 123.3 (2C), 116.4 (2C), 116.2, 113.9, 82.8, 73.3, 59.4,51.8, 50.1, 44.4 (2C), 44.2, 39.3, 37.1, 35.6 30.8, 30.5, 28.6, 26.5,24.2, 24.0, 13.8.

(8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-1-(3-fluoro-4-nitrophenoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene

¹H NMR (300 MHz, CDCl₃): δ 7.88 (dd, J=9.0, 6.0 Hz, 1H), 7.15-7.5 (m,10H), 6.87 (dd, J=10.6, 2.4 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.72 (d,J=2.4 Hz, 1H), 6.66 (tt, J=7.3, 2.3 Hz, 1H), 6.57 (dd, J=8.5, 2.6 Hz,1H), 5.29 (m, 1H), 4.99 (s, 2H), 4.60 (d, J=12.3 Hz, 1H), 4.50 (d,J=12.3 Hz, 1H), 3.54 (dd, J=8.1, 8.1 Hz, 1H), 1.04 (s, 3H), 0.80-3.12(m, 13H). ¹³C NMR (75 MHz, CDCl₃): δ 165.8 (d, J=256.5 Hz), 156.6, 154.2(d, J=11.8 Hz), 139.0, 138.9, 137.2, 135.9 (d, J=3.5 Hz), 128.5 (d,J=2.4 Hz), 128.4 (2C), 128.2 (2C), 127.7, 127.6, 127.41 (2C), 127.37,127.31 (2C), 125.4, 115.0, 112.6, 106.7 (d, J=23.9 Hz), 102.0 (d, J=26.8Hz), 88.5, 76.0, 71.5, 69.8, 50.6, 49.2, 43.0, 39.8, 33.6, 29.8, 27.6,26.9, 23.0, 13.5. ¹⁹F NMR (282 MHz, CDCl₃): δ −100.89.

(8S,9S,11S,13S,14S,17S)-11-(3-Fluoro-4-nitrophenoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol,JD119

¹H NMR (300 MHz, MeOD): δ 7.85 (dd, J=9.0, 6.1 Hz, 1H), 6.86 (dd,J=10.4, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H),6.53 (d, J=2.1 Hz, 1H), 6.39 (m, 1H), 5.29 (m, 1H), 0.93 (s, 3H),0.75-3.85 (m, 14H). ¹³C NMR (75 MHz, MeOD): δ 165.9 (d, J=256.1 Hz),154.1 (d, J=11.3 Hz), 153.4, 139.1, 135.9, 128.4 (d, J=11.3 Hz), 127.1,125.6, 115.8, 112.9, 106.8 (d, J=23.5 Hz), 102.1 (d, J=26.6 Hz), 82.3,76.0, 50.4, 49.1, 42.9, 38.9, 33.9, 30.6, 29.6, 26.8, 23.0, 12.6. ¹⁹FNMR (282 MHz, CDCl₃): δ− 100.74. HR-MS (ESI) calcd for [C₂₄H₂₆FNO₅ H]⁺428.1873, found 428.1879.

(8S,9S,11S,13S,14S,17S)-11-(4-Amino-3-fluorophenoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol,JD120

¹H NMR (300 MHz, CDCl₃): δ 7.26 (s, 2H), 6.71 (m, 2H), 6.49 (m, 2H),6.38 (m, 1H), 5.29 (m, 1H), 0.99 (s, 3H), 0.70-3.80 (m, 18H). ¹³C NMR(75 MHz, CDCl₃): δ 156.5 (d, J=227.6 Hz), 153.5, 146.6 (d, J=9.7 Hz),138.6, 132.1, 127.7, 126.4, 115.434 (d, J=9.4 Hz), 115.427, 113.1, 106.2(d, J=22.2 Hz), 100.2 (d, J=27.1 Hz), 82.2, 74.0, 50.4, 49.1, 42.8,39.0, 34.4, 30.4, 29.6, 27.1, 23.0, 12.8. ¹⁹F NMR (282 MHz, CDCl₃): δ−123.5.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-(piperidin-1-yl)acet-amide

¹H NMR (300 MHz, CDCl₃): δ 8.99 (s, 1H), 8.34 (dd, J=8.9, 6.4 Hz, 1H),7.15-7.50 (m, 10H), 6.68 (m, 5H), 5.28 (m, 1H), 4.94 (s, 2H), 4.50 (d,J=12.3 Hz, 1H), 4.47 (d, J=12.3 Hz, 1H), 2.55 (m, 4H), 1.61 (m, 4H),1.01 (s, 3H), 0.80-3.60 (m, 18H). ¹³C NMR (75 MHz, CDCl₃): δ 168.5,158.9 (d, J=241.2 Hz), 156.7, 147.6 (d, J=9.6 Hz), 138.9, 138.0, 137.1,128.4 (2C), 128.2 (2C), 127.9, 127.8, 127.5, 127.34 (2C), 127.29 (2C),126.2, 124.1 (d, J=3.2 Hz), 120.7 (d, J=8.8 Hz), 115.0, 112.2, 106.3 (d,J=22.5 Hz), 99.6 (d, J=26.7 Hz), 88.4, 73.6, 71.6, 69.7, 63.2, 54.7(2C), 50.5, 48.5, 46.8, 42.7, 40.6, 33.8, 29.1, 27.6, 27.4, 24.6 (2C),23.7, 13.8. HR-MS (ESI) calcd for [C₄₅H₅₁FN₂O₄H]⁺ 703.3911, found703.3939.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-(piperidin-1-yl)acet-amide,JD122

¹H NMR (300 MHz, MeOD): δ 8.10 (dd, J=9.0, 6.3 Hz, 1H), 7.04 (dd,J=10.9, 2.7 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 6.63 (dt, J=8.5, 2.6 Hz,1H), 6.50 (d, J=2.4 Hz, 1H), 6.35 (dd, J=8.6, 2.5 Hz, 1H), 5.37 (m, 1H),2.45 (m, 4H), 1.48 (m, 4H). 0.89 (s, 3H), 0.80-3.80 (m, 18H). ¹³C NMR(75 MHz, MeOD): δ 169.9, 161.2 (d, J=240.8 Hz), 156.1, 150.2 (d, J=10.1Hz), 139.4, 128.2, 127.6, 124.6, 122.6 (d, J=9.3 Hz), 116.3, 113.9,107.0 (d, J=21.8 Hz), 101.6 (d, J=27.6 Hz), 82.7, 75.8, 63.2, 55.8 (2C),51.5, 49.7, 43.9, 40.0, 35.7, 30.4, 30.3, 28.6, 26.5 (2C), 24.5, 24.1,13.9. ¹⁹F NMR (282 MHz, CDCl₃): δ −117.41. HR-MS (ESI) calcd for[C₃₁H₃₉FN₂O₄ H]⁺ 523.2972, found 523.2956.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-(pyrrolidin-1-yl)ac-etamide

¹H NMR (300 MHz, CDCl₃): δ 9.00 (s, 1H), 8.37 (dd, J=8.9, 6.4 Hz, 1H),7.25-7.50 (m, 10H), 6.76 (d, J=2.5 Hz, 1H), 6.72 (d, J=4.2 Hz, 1H), 6.69(d, J=2.5 Hz, 1H), 6.64 (m, 1H), 6.56 (dd, J=8.6, 2.6 Hz, 1H), 5.19 (m,1H), 4.97 (s, 2H), 4.56 (d, J=12.3 Hz, 1H), 4.50 (d, J=12.3 Hz, 1H),2.59 (m, 4H), 1.75 (m, 4H), 0.99 (s, 3H), 0.80-3.60 (m, 16H). ¹³C NMR(75 MHz, CDCl₃): δ 168.7, 159.0 (d, J=241.0 Hz), 156.6, 147.5 (d, J=9.8Hz), 138.9, 138.0, 137.1, 128.5 (2C), 128.3 (2C), 127.9, 127.8, 127.41,127.39 (2C), 127.32 (2C), 126.1, 124.1 (d, J=3.0 Hz), 120.3 (d, J=9.2Hz), 115.0, 112.3, 106.2 (d, J=22.1 Hz), 99.4 (d, J=26.8 Hz), 88.4,73.7, 71.6, 69.7, 60.5, 54.6 (2C), 50.5, 48.6, 42.8, 39.7, 33.9, 29.3,27.6, 27.3, 24.2 (2C), 23.2, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −116.81.HR-MS (ESI) calcd for [C₄₄H₄₉FN₂O₄ H]⁺ 689.3755, found 689.3782.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-(pyrrolidin-1-yl)acet-amide,JD125

¹H NMR (300 MHz, MeOD): δ 8.16 (dd, J=8.9, 6.4 Hz, 1H), 6.99 (dd,J=10.7, 2.4 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.61 (td, J=8.7, 2.5 Hz,1H), 6.51 (s, 1H), 6.35 (d, J=8.5 Hz, 1H), 5.32 (m, 1H), 2.55 (m, 4H),1.79 (m, 4H), 0.86 (s, 3H), 0.80-3.75 (m, 16H). ¹³C NMR (75 MHz, MeOD):δ 170.8, 160.9 (d, J=245.4 Hz), 156.1, 149.9 (d, J=10.1 Hz), 139.4,128.1, 127.5, 124.7 (d, J=3.3 Hz), 121.8 (d, J=9.6 Hz), 116.2, 113.9,106.8 (d, J=22.0 Hz), 101.2 (d, J=27.4 Hz), 82.7, 75.7, 61.1, 55.6 (2C),51.4, 49.8, 43.9, 39.9, 35.7, 30.7, 30.5, 28.5, 25.2 (2C), 24.1, 13.9.¹⁹F NMR (282 MHz, MeOD): δ −117.59.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-morpholinoacet-amide

¹H NMR (300 MHz, CDCl₃): δ 8.76 (s, 1H), 8.30 (dd, J=9.1, 6.5 Hz, 1H),7.20-7.40 (m, 10H), 6.45-6.80 (m, 5H), 5.15 (m, 1H), 4.91 (s, 2H), 4.50(d, J=12.1 Hz, 1H), 4.43 (d, J=12.1 Hz, 1H), 3.48 (m, 4H), 2.55 (m, 4H),0.94 (s, 3H), 0.80-3.75 (m, 16H). ¹³C NMR (75 MHz, CDCl₃): δ 168.7,159.0 (d, J=242.1 Hz), 156.5, 147.4 (d, J=9.6 Hz), 138.7, 137.7, 136.9,128.2 (2C), 128.0 (2C), 127.7, 127.6, 127.2, 127.14 (2C), 127.12 (2C),126.1, 123.7 (d, J=3.3 Hz), 120.4 (d, J=9.6 Hz), 114.6, 112.3, 106.2 (d,J=21.4 Hz), 99.6 (d, J=26.2 Hz), 88.1, 73.7, 71.4, 69.5, 66.4 (2C),62.7, 53.5 (2C), 50.2, 48.2, 42.5, 33.9, 29.4, 27.4, 27.1, 24.2, 23.0,13.6. ¹⁹F NMR (282 MHz, CDCl₃): δ −116.34. HR-MS (ESI) calcd for[C₄₄H₄₉FN₂O₅ H]⁺ 705.3704, found 705.3690.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-morpholinoacetamide,JD126

¹H NMR (300 MHz, MeOD): δ 8.17 (dd, J=9.0, 6.3 Hz, 1H), 7.04 (dd,J=10.9, 2.7 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.63 (dt, J=8.3, 2.7 Hz,1H), 6.51 (d, J=2.5 Hz, 1H), 6.35 (dd, J=8.5, 2.6 Hz, 1H), 5.37 (m, 1H),3.30 (m, 4H), 2.39 (m, 4H), 0.89 (s, 3H), 0.80-3.80 (m, 16H). ¹³C NMR(75 MHz, MeOD): δ 170.0, 161.2 (d, J=240.6 Hz), 156.2, 149.9 (d, J=9.8Hz), 139.3, 128.2, 127.6, 124.7 (d, J=3.1 Hz), 122.2 (d, J=9.5 Hz),116.3, 114.0, 106.9 (d, J=22.2 Hz), 101.5 (d, J=27.7 Hz), 82.7, 75.6,67.8 (2C), 63.5, 54.8 (2C), 51.5, 49.6, 43.9, 39.9, 35.9, 30.4, 30.3,28.6, 24.1, 13.9. ¹⁹F NMR (282 MHz, MeOD): δ −117.53. HR-MS (ESI) calcdfor [C₃₀H₃₇FN₂O₅ H]⁺ 525.2765, found 525.2782.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-(dimethylamino)ac-etamide

¹H NMR (300 MHz, CDCl₃): δ 9.25 (s, 1H), 8.35 (dd, J=8.7, 6.5 Hz, 1H),7.15-7.55 (m, 10H), 6.50-6.85 (m, 5H), 5.19 (m, 1H), 4.97 (s, 2H), 4.57(d, J=12.0 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 2.11 (s, 6H), 0.97 (s, 3H),0.80-3.60 (m, 16H). ¹³C NMR (75 MHz, CDCl₃): δ 168.2, 159.8 (d, J=287.4Hz), 156.6, 147.3 (d, J=9.6 Hz), 138.9, 138.0, 137.1, 128.4 (2C), 128.2(2C), 128.0, 127.8, 127.4 (2C), 127.31, 127.3 (2C), 126.1, 124.0 (d,J=2.7 Hz), 119.9 (d, J=9.5 Hz), 115.0, 112.4, 106.1 (d, J=21.6 Hz), 99.1(d, J=26.8 Hz), 88.4, 73.1, 71.6, 69.7, 63.6, 50.4, 48.7, 45.7 (2C),42.7, 39.3, 34.1, 29.7, 27.6, 27.4, 23.1, 13.5. ¹⁹F NMR (282 MHz,CDCl₃): δ −116.79. HR-MS (ESI) calcd for [C₄₂H₄₇FN₂O₄ H]⁺ 663.3598,found 663.3624.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-2-(dimethylamino)acet-amide,JD129

¹H NMR (300 MHz, MeOD): δ 8.14 (dd, J=8.9, 6.3 Hz, 1H), 6.98 (dd,J=10.8, 2.6 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 6.61 (dt, J=8.6, 2.7 Hz,1H), 6.50 (d, J=2.5 Hz, 1H), 6.37 (dd, J=8.5, 2.6 Hz, 1H), 5.33 (m, 1H),3.70 (dd, J=8.3, 8.3 Hz, 1H), 2.16 (s, 6H), 0.84 (s, 3H), 0.80-3.75 (m,15H). ¹³C NMR (75 MHz, MeOD): δ 170.4, 161.0 (d, J=241.6 Hz), 156.1,149.6 (d, J=10.2 Hz), 139.4, 128.2, 127.5, 124.7 (d, J=3.1 Hz), 121.4(d, J=8.7 Hz), 116.3, 114.0, 106.6 (d, J=22.4 Hz), 101.0 (d, J=27.8 Hz),82.7, 75.1, 64.2, 51.4, 49.9, 46.1 (2C), 43.9, 39.5, 35.9, 30.8, 30.4,28.6, 24.1, 13.6. ¹⁹F NMR (282 MHz, MeOD): δ −117.74. HR-MS (ESI) calcdfor [C₂₈H₃₅FN₂O₄ H]⁺ 483.2659, found 483.2660.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-(piperidin-1-yl)pro-panamide

¹H NMR (300 MHz, CDCl₃): δ 8.01 (s, 1H), 7.20-7.60 (m, 11H), 6.75 (m,3H), 6.61 (m, 2H), 5.06 (m, 1H), 4.98 (s, 2H), 4.58 (d, J=12.0 Hz, 1H),4.50 (d, J=12.0 Hz, 1H), 2.58 (m, 4H), 1.66 (m, 4H), 1.00 (s, 3H),0.80-3.60 (m, 20H). ¹³C NMR (75 MHz, CDCl₃): δ 168.4, 159.3 (d, J=243.2Hz), 156.6, 149.1 (d, J=9.6 Hz), 138.9, 138.7, 137.0, 128.4 (2C), 128.2(2C), 128.0, 127.8, 127.4, 127.30 (2C), 127.28 (2C), 126.3, 123.8 (d,J=3.2 Hz), 121.7 (d, J=9.0 Hz), 115.5, 112.2, 106.8 (d, J=22.2 Hz),100.8 (d, J=27.1 Hz), 88.4, 76.9, 71.6, 69.7, 53.5 (2C), 53.3, 50.2,49.1, 42.9, 40.8, 34.2, 33.0, 29.7, 27.6, 26.9, 24.3 (2C), 23.2, 22.9,13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −115.87. HR-MS (ESI) calcd for[C₄₆H₅₃FN₂O₄ H]⁺ 717.4067, found 717.4052.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-(piperidin-1-yl)propan-amide,JD130

¹H NMR (500 MHz, MeOD): δ 7.71 (dd, J=8.8, 6.3 Hz, 1H), 7.02 (dd,J=10.6, 2.4 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.63 (td, J=8.5, 2.5 Hz,1H), 6.55 (d, J=2.1 Hz, 1H), 6.38 (dd, J=8.5, 2.3 Hz, 1H), 5.24 (m, 1H),3.70 (dd, J=8.3, 8.3 Hz, 1H), 2.80 (m, 4H), 1.70 (m, 4H), 0.87 (s, 3H),0.78-3.40 (m, 19H). ¹³C NMR (125 MHz, MeOD): δ 170.6, 161.7 (d, J=242.0Hz), 156.2, 152.1 (d, J=10.2 Hz), 139.8, 128.3, 127.9, 125.0 (d, J=9.7Hz), 124.4 (d, J=3.1 Hz), 116.5, 114.3, 107.3 (d, J=22.9 Hz), 102.4 (d,J=26.9 Hz), 82.7, 77.7, 54.73 (2C), 54.65, 51.3, 50.3, 44.1, 40.7, 35.9,32.6, 30.9, 30.4, 28.3, 25.3 (2C), 24.0, 23.8, 13.7. ¹⁹F NMR (282 MHz,MeOD): δ −116.52. HR-MS (ESI) calcd for [C₃₂H₄₁FN₂O₄ H]⁺ 537.3129, found537.3132.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-(pyrrolidin-1-yl)propanamide

¹H NMR (500 MHz, CDCl₃): δ 9.47 (br s, 1H), 7.98 (dd, J=8.9, 6.3 Hz,1H), 7.20-7.45 (m, 9H), 7.13 (s, 1H), 6.84 (d, J=2.1 Hz, 1H), 6.78 (dd,J=10.1, 2.5 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.64 (dt, J=8.7, 2.6 Hz,1H), 6.55 (dd, J=8.6, 2.4 Hz, 1H), 5.03 (m, 1H), 5.01 (d, J=11.7 Hz,1H), 4.96 (d, J=11.7 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 4.50 (d, J=12.2Hz, 1H), 3.52 (dd, J=8.1, 8.1 Hz, 1H), 2.90 (m, 4H), 1.88 (m, 4H), 1.00(s, 3H), 0.80-3.20 (m, 17H). ¹³C NMR (125 MHz, CDCl₃): δ 167.3, 159.3(d, J=243.2 Hz), 156.5, 149.2 (d, J=9.7 Hz), 139.1, 138.9, 136.9, 128.5(2C), 128.3 (2C), 128.2, 127.8, 127.4, 127.33 (2C), 127.30 (2C), 126.3,123.7 (d, J=3.3 Hz), 121.5 (d, J=9.6 Hz), 115.7, 112.1, 107.0 (d, J=21.5Hz), 101.1 (d, J=26.7 Hz), 88.3, 77.7, 71.6, 69.7, 53.2 (2C), 50.5,50.1, 49.2, 43.0, 41.1, 34.1, 33.4, 29.7, 27.6, 26.8, 23.2 (2C), 22.9,13.8. ¹⁹F NMR (282 MHz, CDCl₃): δ −115.73. HR-MS (ESI) calcd for[C₄₅H₅₁FN₂O₄ H]⁺ 703.3911, found 703.3906.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-(pyrrolidin-1-yl)propan-amide,JD132

¹H NMR (500 MHz, MeOD): δ 7.75 (dd, J=8.8, 6.3 Hz, 1H), 7.03 (dd,J=10.6, 2.6 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.64 (td, J=8.6, 2.6 Hz,1H), 6.57 (d, J=2.3 Hz, 1H), 6.38 (dd, J=8.5, 2.5 Hz, 1H), 5.23 (m, 1H),3.71 (dd, J=8.3, 8.3 Hz, 1H), 3.30 (dt, J=3.2, 1.6 Hz, 3H), 3.17 (m,4H), 2.02 (m, 4H), 0.88 (s, 3H), 0.80-3.10 (m, 13H). ¹³C NMR (125 MHz,MeOD): δ 169.8, 161.7 (d, J=243.9 Hz), 156.2, 152.1 (d, J=10.2 Hz),139.9, 128.4, 127.9, 124.8 (d, J=9.8 Hz), 124.4 (d, J=3.2 Hz), 116.5,114.3, 107.3 (d, J=22.5 Hz), 102.5 (d, J=26.5 Hz), 82.7, 78.1, 55.2(2C), 52.1, 51.3, 50.3, 44.1, 40.8, 35.8, 33.2, 30.9, 30.4, 28.3, 24.1(2C), 24.0, 13.7. ¹⁹F NMR (282 MHz, MeOD): δ −116.52.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-(dimethylamino)-propanamide

¹H NMR (500 MHz, CDCl₃): δ 8.96 (br s, 1H), 8.01 (dd, J=8.9, 6.3 Hz,1H), 7.43 (s, 1H), 7.20-7.40 (m, 9H), 6.79 (d, J=2.5 Hz, 1H), 6.77 (dd,J=7.9, 2.6 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.64 (td, J=8.6, 2.6 Hz,1H), 6.56 (dd, J=8.6, 2.6 Hz, 1H), 5.06 (m, 1H), 4.98 (d, J=11.5 Hz,1H), 4.96 (d, J=11.5 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 4.50 (d, J=12.2Hz, 1H), 3.52 (dd, J=8.2, 8.2 Hz, 1H), 2.35 (s, 6H), 1.00 (s, 3H),0.80-3.00 (m, 17H). ¹³C NMR (125 MHz, CDCl₃): δ 168.1, 159.3 (d, J=282.8Hz), 156.6, 149.0 (d, J=9.8 Hz), 138.9, 138.7, 136.9, 128.5 (2C), 128.3(2C), 128.1, 127.9, 127.4, 127.37 (2C), 127.34 (2C), 126.4, 123.8 (d,J=3.1 Hz), 121.7 (d, J=9.4 Hz), 115.6, 112.2, 106.9 (d, J=21.1 Hz),100.9 (d, J=27.5 Hz), 88.3, 76.9, 71.6, 69.7, 53.5, 50.2, 49.1, 43.5(2C), 42.9, 40.8, 34.1, 33.0, 29.6, 27.6, 26.9, 23.0, 13.7. ¹⁹F NMR (282MHz, CDCl₃): δ −115.94. HR-MS (ESI) calcd for [C₄₃H₄₉FN₂O₄ H]⁺ 677.3755,found 677.3738.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-(dimethylamino)propan-amide,JD133

¹H NMR (500 MHz, MeOD): δ 7.74 (dd, J=8.8, 6.3 Hz, 1H), 6.98 (dd,J=10.7, 2.5 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 6.64 (td, J=8.6, 2.5 Hz,1H), 6.54 (d, J=2.2 Hz, 1H), 6.38 (dd, J=8.5, 2.4 Hz, 1H), 5.20 (m, 1H),3.56 (dd, J=8.2, 8.2 Hz, 1H), 2.46 (s, 6H), 0.94 (s, 3H), 0.80-3.40 (m,15H). ¹³C NMR (125 MHz, MeOD): δ 169.4, 161.6 (d, J=242.9 Hz), 156.2,152.0 (d, J=10.4 Hz), 139.9, 128.4, 127.9, 124.9 (d, J=9.7 Hz), 124.3(d, J=3.3 Hz), 116.5, 114.3, 107.3 (d, J=22.5 Hz), 102.4 (d, J=26.5 Hz),82.7, 77.8, 55.2, 51.3, 50.3, 44.2 (2C), 44.1, 40.7, 35.8, 32.4, 30.8,30.4, 28.3, 24.9, 14.3. ¹⁹F NMR (282 MHz, MeOD): δ −116.56.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-morpholinopropan-amide

¹H NMR (500 MHz, CDCl₃): δ 9.12 (s, 1H), 8.04 (dd, J=8.8, 6.4 Hz, 1H),7.20-7.50 (m, 10H), 6.79 (m, 1H), 6.76 (m, 1H), 6.74 (m, 1H), 6.66 (m,1H), 6.57 (m, 1H), 5.27 (m, 1H), 4.98 (s, 2H), 4.59 (d, J=12.5 Hz, 1H),4.52 (d, J=12.5 Hz, 1H), 3.65 (t, J=4.1 Hz, 4H), 2.93 (t, J=4.1 Hz, 4H),0.99 (s, 3H), 0.75-3.40 (m, 18H). ¹³C NMR (125 MHz, CDCl₃): δ 169.0,159.2 (d, J=245.3 Hz), 156.7, 148.8 (d, J=9.8 Hz), 138.8, 138.2, 136.8,128.43 (2C), 128.41, 128.2 (2C), 127.8, 127.4, 127.30 (2C), 127.27 (2C),126.3, 123.8 (d, J=2.9 Hz), 121.7 (d, J=9.4 Hz), 115.4, 112.3, 106.8 (d,J=21.9 Hz), 100.8 (d, J=12.7 Hz), 88.2, 76.5, 71.6, 69.7, 66.6 (2C),54.0, 53.1 (2C), 50.0, 49.0, 42.8, 40.6, 34.4, 34.2, 29.8, 27.5, 26.9,22.9, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −116.07. HR-MS (ESI) calcd for[C₄₅H₅₁FN₂O₅ H]⁺ 719.3860, found 719.3887.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-3-morpholinopropan-amide,JD134

¹H NMR (500 MHz, MeOD): δ 7.69 (dd, J=8.5, 6.5 Hz, 1H), 7.02 (dd,J=10.7, 2.7 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.63 (td, J=8.4, 2.1 Hz,1H), 6.54 (s, 1H), 6.39 (dd, J=8.3, 1.9 Hz, 1H), 5.25 (m, 1H), 3.65 (m,4H), 2.55 (m, 4H), 0.85 (s, 3H), 0.70-3.80 (m, 18H). ¹³C NMR (125 MHz,MeOD): δ 171.8, 161.7 (d, J=242.1 Hz), 156.3, 152.0 (d, J=10.3 Hz),139.7, 128.2, 127.8, 125.2 (d, J=9.7 Hz), 124.3 (d, J=3.2 Hz), 116.6,114.3, 107.3 (d, J=22.3 Hz), 102.3 (d, J=27.3 Hz), 82.7, 77.3, 67.4(2C), 55.2, 54.2 (2C), 51.3, 50.2, 44.0, 40.4, 36.0, 34.1, 30.9, 30.4,28.3, 24.0, 13.7. ¹⁹F NMR (282 MHz, MeOD): δ −116.52. HR-MS (ESI) calcdfor [C₄₅H₅₄N₂O₄ H]⁺ 687.4162, found 687.4188.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-morpholinobutan-amide

¹H NMR (500 MHz, CDCl₃): δ 9.89 (s, 1H), 8.12 (dd, J=8.8, 6.4 Hz, 1H),7.20-7.50 (m, 9H), 6.84 (s, 1H), 6.76 (dd, J=5.9, 2.4 Hz, 1H), 6.74 (m,2H), 6.64 (td, J=8.6, 2.4 Hz, 1H), 6.57 (dd, J=8.6, 2.4 Hz, 1H), 5.06(m, 1H), 4.96 (s, 2H), 4.60 (d, J=12.2 Hz, 1H), 4.51 (d, J=12.2 Hz, 1H),3.65 (t, J=3.2 Hz, 4H), 2.42 (t, J=3.2 Hz, 4H), 0.98 (s, 3H), 0.70-3.70(m, 20H). ¹³C NMR (125 MHz, CDCl₃): δ 169.9, 158.9 (d, J=242.4 Hz),156.8, 148.3 (d, J=9.8 Hz), 138.9, 138.5, 136.8, 128.5 (2C), 128.3 (2C),127.9, 127.85, 127.5, 127.4 (2C), 127.3 (2C), 126.3, 124.3 (d, J=2.9Hz), 120.6 (d, J=9.3 Hz), 115.4, 112.4, 107.0 (d, J=21.5 Hz), 100.7 (d,J=26.1 Hz), 88.3, 77.0, 71.7, 69.7, 66.5 (2C), 57.8, 53.2 (2C), 50.1,49.3, 43.0, 40.9, 34.9, 34.5, 29.9, 27.6, 26.8, 23.0, 21.6, 13.8. ¹⁹FNMR (282 MHz, CDCl₃): δ −116.60. HR-MS (ESI) calcd for [C₄₆H₅₃FN₂O₅ H]⁺733.4017, found 733.4049.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-morpholinobutanamide,JD135

¹H NMR (500 MHz, MeOD): δ 7.77 (dd, J=8.9, 6.3 Hz, 1H), 7.01 (dd,J=10.6, 2.6 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.63 (td, J=8.6, 2.6 Hz,1H), 6.55 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.5, 2.5 Hz, 1H), 5.25 (m, 1H),3.69 (t, J=4.8 Hz, 4H), 2.56 (d, J=4.8 Hz, 4H), 0.86 (s, 3H), 0.75-3.30(m, 20H). ¹³C NMR (125 MHz, MeOD): δ 173.0, 161.4 (d, J=243.5 Hz),156.3, 151.5 (d, J=10.2 Hz), 139.8, 128.2, 127.8, 124.7 (d, J=3.0 Hz),124.1 (d, J=9.7 Hz), 116.6, 114.4, 107.3 (d, J=22.6 Hz), 102.3 (d,J=26.7 Hz), 82.7, 77.8, 67.3 (2C), 59.0, 54.4 (2C), 51.2, 50.3, 44.1,40.6, 36.1, 35.5, 31.0, 30.4, 28.2, 23.9, 22.7, 13.8. ¹⁹F NMR (282 MHz,MeOD): δ −116.93.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-(piperidin-1-yl)butanamide

¹H NMR (300 MHz, CDCl₃): δ 9.03 (br. s, 1H), 8.02 (dd, J=8.9, 6.3 Hz,1H), 7.15-7.40 (m, 10H), 6.78 (d, J=2.5 Hz, 1H), 6.76 (s, 1H), 6.72 (d,J=8.6 Hz, 1H), 6.63 (td, J=8.6, 2.6 Hz, 1H), 6.55 (dd, J=8.5, 2.4 Hz,1H), 5.03 (m, 1H), 5.00 (d, J=11.8 Hz, 1H), 4.96 (d, J=11.8 Hz, 1H),4.59 (d, J=12.2 Hz, 1H), 4.50 (d, J=12.2 Hz, 1H), 3.52 (dd, J=8.0, 8.0Hz, 1H), 2.76 (m, 4H), 1.78 (m, 4H), 0.98 (s, 3H), 0.78-3.00 (m, 21H).¹³C NMR (75 MHz, CDCl₃): δ 168.8, 159.1 (d, J=243.1 Hz), 156.7, 148.7(d, J=9.8 Hz), 138.9, 138.8, 136.8, 128.5 (2C), 128.3 (2C), 128.0,127.9, 127.5, 127.4 (2C), 127.3 (2C), 126.4, 124.0 (d, J=2.9 Hz), 120.6(d, J=9.3 Hz), 115.4, 112.6, 107.1 (d, J=21.9 Hz), 101.1 (d, J=26.9 Hz),88.3, 77.8, 71.6, 69.8, 56.6, 53.0 (2C), 50.1, 49.3, 43.0, 41.2, 34.4,33.3, 30.0, 27.6, 27.0, 26.7, 23.0 (2C), 22.7, 22.4, 13.9. ¹⁹F NMR (282MHz, CDCl₃): δ −116.13. HR-MS (ESI) calcd for [C₄₇H₅₅FN₂O₄ H]⁺ 731.4224,found 731.4240.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-(piperidin-1-yl)butan-amide,JD137

¹H NMR (500 MHz, MeOD): δ 7.74 (dd, J=8.9, 6.3 Hz, 1H), 7.03 (dd,J=10.6, 2.6 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 6.64 (td, J=8.6, 2.6 Hz,1H), 6.56 (d, J=2.5 Hz, 1H), 6.38 (dd, J=8.5, 2.6 Hz, 1H), 5.24 (m, 1H),3.71 (dd, J=8.3, 8.3 Hz, 1H), 2.59 (m, 4H), 1.85 (m, 4H), 0.88 (s, 3H),0.80-3.40 (m, 21H). ¹³C NMR (125 MHz, MeOD): δ 172.1, 161.6 (d, J=242.5Hz), 156.2, 152.1 (d, J=10.2 Hz), 140.0, 128.34, 127.9, 124.62 (d, J=9.3Hz), 124.56 (d, J=3.0 Hz), 116.5, 114.3, 107.4 (d, J=22.4 Hz), 102.5 (d,J=27.6 Hz), 82.7, 78.2, 58.0, 54.4 (2C), 51.3, 50.4, 44.2, 40.9, 36.0,34.1, 31.0, 30.4, 28.3, 24.5 (2C), 24.0, 22.8, 20.6, 13.7. ¹⁹F NMR (376MHz, MeOD): δ −118.84. HR-MS (ESI) calcd for [C₃₃H₄₃FN₂O₄ H]⁺ 551.3285,found 551.3287.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-(pyrrolidin-1-yl)bu-tanamide

¹H NMR (500 MHz, CDCl₃): δ 11.31 (s, 1H), 8.00 (dd, J=8.9, 6.3 Hz, 1H),7.20-7.45 (m, 10H), 6.78 (d, J=1.8 Hz, 1H), 6.73 (m, 2H), 6.63 (td,J=8.6, 2.5 Hz, 1H), 6.54 (dd, J=8.6, 2.4 Hz, 1H), 5.03 (m, 1H), 4.99 (d,J=11.6 Hz, 1H), 4.95 (d, J=11.7 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 4.49(d, J=12.2 Hz, 1H), 3.52 (dd, J=8.1, 8.1 Hz, 1H), 2.92 (m, 4H), 1.92 (m,4H), 0.98 (s, 3H), 0.80-3.20 (m, 19H). ¹³C NMR (125 MHz, CDCl₃): δ168.6, 159.1 (d, J=243.0 Hz), 156.7, 148.8 (d, J=9.9 Hz), 138.9, 138.8,136.8, 128.5 (2C), 128.3 (2C), 128.1, 127.9, 127.5, 127.4 (2C), 127.3(2C), 126.4, 123.9 (d, J=3.1 Hz), 120.5 (d, J=9.4 Hz), 115.4, 112.7,107.1 (d, J=21.7 Hz), 101.2 (d, J=26.4 Hz), 88.3, 78.0, 71.6, 69.9,54.5, 53.2 (2C), 50.0, 49.3, 43.0, 41.2, 34.5, 32.8, 30.0, 27.6, 26.7,23.2 (2C), 22.9, 20.8, 13.9. ¹⁹F NMR (282 MHz, CDCl₃): δ −115.96. HR-MS(ESI) calcd for [C₄₆H₅₃FN₂O₄ H]⁺ 717.4067, found 717.4094.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-(pyrrolidin-1-yl)butan-amide,JD138

¹H NMR (500 MHz, MeOD): δ 7.75 (dd, J=8.9, 6.3 Hz, 1H), 7.03 (dd,J=10.6, 2.5 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.63 (td, J=8.6, 2.5 Hz,1H), 6.57 (d, J=2.2 Hz, 1H), 6.38 (dd, J=8.5, 2.4 Hz, 1H), 5.24 (m, 1H),3.71 (dd, J=8.2, 8.2 Hz, 1H), 2.57 (m, 4H), 1.89 (m, 4H), 0.88 (s, 3H),0.80-3.40 (m, 19H). ¹³C NMR (125 MHz, MeOD): δ 171.8, 161.6 (d, J=242.7Hz), 156.2, 152.0 (d, J=10.1 Hz), 140.0, 128.3, 127.9, 124.6 (d, J=3.3Hz), 124.5 (d, J=9.8 Hz), 116.5, 114.3, 107.3 (d, J=22.1 Hz), 102.5 (d,J=27.0 Hz), 82.7, 78.2, 55.8, 55.2 (2C), 51.3, 50.4, 44.2, 40.9, 36.0,33.8, 31.0, 30.4, 28.3, 24.02 (2C), 23.96, 22.4, 13.7. ¹⁹F NMR (282 MHz,MeOD): δ −116.87. HR-MS (ESI) calcd for [C₃₂H₄₁FN₂O₄ H]⁺ 537.3129, found537.3135.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-(dimethylamino)bu-tanamide

¹H NMR (500 MHz, CDCl₃): δ 8.06 (dd, J=8.8, 6.4 Hz, 1H), 7.20-7.50 (m,10H), 6.82 (s, 1H), 6.77 (m, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.63 (td,J=8.6, 2.4 Hz, 1H), 6.56 (dd, J=8.5, 2.2 Hz, 1H), 5.05 (m, 1H), 4.97 (s,2H), 4.60 (d, J=12.2 Hz, 1H), 4.50 (d, J=12.2 Hz, 1H), 3.52 (dd, J=8.1,8.1 Hz, 1H), 2.41 (s, 6H), 0.98 (s, 3H), 0.80-3.00 (m, 19H). ¹³C NMR(125 MHz, CDCl₃): δ 169.3, 159.1 (d, J=242.8 Hz), 156.8, 148.6 (d, J=9.8Hz), 138.9, 138.7, 136.9, 128.6 (2C), 128.3 (2C), 128.02, 127.95, 127.5,127.41 (2C), 127.38 (2C), 126.4, 124.1 (d, J=3.2 Hz), 120.6 (d, J=9.5Hz), 115.4, 112.6, 107.0 (d, J=21.7 Hz), 100.9 (d, J=27.1 Hz), 88.3,77.5, 71.7, 69.9, 57.7, 50.1, 49.3, 43.8, 43.0 (2C), 41.1, 34.5, 33.8,29.9, 27.6, 26.8, 23.0, 21.1, 13.9. ¹⁹F NMR (282 MHz, CDCl₃): δ −116.34.HR-MS (ESI) calcd for [C₄₄H₅₁FN₂O₄ H]⁺ 691.3911, found 691.3903.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-4-(dimethylamino)butan-amide,JD139

¹H NMR (500 MHz, MeOD): δ 7.77 (dd, J=8.8, 6.3 Hz, 1H), 7.02 (dd,J=10.6, 2.4 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.63 (td, J=8.7, 2.6 Hz,1H), 6.54 (d, J=2.0 Hz, 1H), 6.38 (dd, J=8.5, 2.2 Hz, 1H), 5.26 (m, 1H),3.70 (dd, J=8.3, 8.3 Hz, 1H), 2.30 (s, 6H), 0.87 (s, 3H), 0.80-3.40 (m,19H). ¹³C NMR (125 MHz, MeOD): δ 172.8, 161.4 (d, J=251.5 Hz), 156.4,151.7 (d, J=10.2 Hz), 139.8, 128.1, 127.8, 124.8 (d, J=3.0 Hz), 124.2(d, J=9.7 Hz), 116.6, 114.4, 107.3 (d, J=22.3 Hz), 102.3 (d, J=27.0 Hz),82.7, 77.9, 59.7, 51.3, 50.4, 45.2 (2C), 44.2, 40.8, 36.1, 35.3, 31.0,30.4, 28.3, 24.0, 23.8, 13.3. ¹⁹F NMR (282 MHz, MeOD): δ −117.24. HR-MS(ESI) calcd for [C₃₀H₃₉FN₂O₄ H]⁺ 511.2972, found 511.2961.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-(piperidin-1-yl)pen-tanamide

¹H NMR (500 MHz, CDCl₃): δ 8.63 (br s, 1H), 8.06 (dd, J=8.9, 6.3 Hz,1H), 7.32 (m, 9H), 6.78 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 6.75 (dd,J=10.4, 2.5 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 6.60 (td, J=8.7, 2.4 Hz,1H), 6.53 (dd, J=8.6, 2.3 Hz, 1H), 5.01 (m, 1H), 4.97 (d, J=11.5 Hz,1H), 4.94 (d, J=11.5 Hz, 1H), 4.57 (d, J=12.2 Hz, 1H), 4.46 (d, J=12.2Hz, 1H), 2.69 (m, 4H), 1.72 (m, 4H), 0.96 (s, 3H), 0.80-3.60 (m, 24H).¹³C NMR (125 MHz, CDCl₃): δ 169.4, 158.8 (d, J=243.3 Hz), 156.6, 148.1(d, J=9.8 Hz), 138.78, 138.77, 136.8, 128.4 (2C), 128.2 (2C), 128.0,127.8, 127.4 (2C), 127.3, 127.2 (2C), 126.2, 124.0 (d, J=3.0 Hz), 120.4(d, J=9.1 Hz), 115.5, 112.0, 106.8 (d, J=22.5 Hz), 100.7 (d, J=26.6 Hz),88.2, 77.2, 71.5, 69.7, 56.8, 52.8 (2C), 49.9, 49.1, 42.8, 40.8, 35.9,34.3, 29.8, 27.4, 26.6, 23.0, 22.8, 22.4 (2C), 22.2, 22.0, 13.8. ¹⁹F NMR(282 MHz, CDCl₃): δ −116.30. HR-MS (ESI) calcd for [C₄₈H₅₇FN₂O₄ H]⁺745.4380, found 745.4357.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-(piperidin-1-yl)pentan-amide,JD140

¹H NMR (500 MHz, MeOD): δ 7.81 (dd, J=8.9, 6.3 Hz, 1H), 7.01 (dd,J=10.5, 2.5 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.63 (td, J=8.6, 2.6 Hz,1H), 6.59 (d, J=2.3 Hz, 1H), 6.39 (dd, J=8.5, 2.4 Hz, 1H), 5.22 (m, 1H),3.71 (dd, J=8.3, 8.3 Hz, 1H), 2.57 (m, 4H), 1.86 (m, 4H), 0.86 (s, 3H),0.80-3.40 (m, 23H). ¹³C NMR (125 MHz, MeOD): δ 172.6, 161.3 (d, J=241.8Hz), 156.3, 151.5 (d, J=10.1 Hz), 139.9, 128.2, 127.8, 124.8 (d, J=3.2Hz), 123.8 (d, J=10.0 Hz), 116.6, 114.3, 107.3 (d, J=21.8 Hz), 102.3 (d,J=29.8 Hz), 82.6, 78.1, 57.8, 54.2 (2C), 51.2, 50.3, 44.1, 40.8, 36.6,36.0, 31.0, 30.4, 28.2, 24.5, 24.3 (2C), 23.9, 23.3, 22.7, 13.7. ¹⁹F NMR(376 MHz, MeOD): δ −117.03. HR-MS (ESI) calcd for [C₃₄H₄₅FN₂O₄ H]⁺565.3442, found 565.3444.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-morpholinopentan-amide

¹H NMR (500 MHz, CDCl₃): δ 8.13 (dd, J=8.8, 6.4 Hz, 1H), 7.20-7.40 (m,10H), 6.81 (s, 1H), 6.76 (m, 3H), 6.64 (td, J=8.7, 2.4 Hz, 1H), 6.57(dd, J=8.6, 2.4 Hz, 1H), 5.05 (m, 1H), 4.96 (s, 2H), 4.61 (d, J=12.2 Hz,1H), 4.50 (d, J=12.2 Hz, 1H), 3.71 (t, J=4.4 Hz, 4H), 3.53 (dd, J=8.1,8.1 Hz, 1H), 2.45 (t, J=4.4 Hz, 4H), 0.98 (s, 3H), 0.80-3.00 (m, 21H).¹³C NMR (125 MHz, CDCl₃): δ 170.1, 158.9 (d, J=242.5 Hz), 156.8, 148.3(d, J=9.7 Hz), 138.9, 138.4, 136.8, 128.5 (2C), 128.3 (2C), 127.87,127.86, 127.5, 127.4 (2C), 127.3 (2C), 126.3, 124.2 (d, J=3.0 Hz), 120.5(d, J=9.3 Hz), 115.5, 112.3, 106.9 (d, J=21.6 Hz), 100.6 (d, J=27.4 Hz),88.3, 76.9, 71.6, 69.7, 66.4 (2C), 58.2, 53.2 (2C), 50.0, 49.2, 42.9,40.8, 37.1, 34.5, 30.0, 27.6, 26.8, 25.5, 23.1, 23.0, 13.8. ¹⁹F NMR (282MHz, CDCl₃): δ −116.61. HR-MS (ESI) calcd for [C₄₇H₅₅FN₂O₅ H]⁺ 747.4173,found 747.4177.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-morpholinopentan-amide,JD141

¹H NMR (500 MHz, MeOD): δ 7.81 (dd, J=8.9, 6.3 Hz, 1H), 7.00 (dd,J=10.6, 2.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.62 (td, J=8.6, 2.6 Hz,1H), 6.56 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.5, 2.5 Hz, 1H), 5.22 (m, 1H),3.76 (t, J=4.6 Hz, 4H), 3.70 (dd, J=8.3, 8.3 Hz, 1H), 2.59 (t, J=4.6 Hz,4H), 0.86 (s, 3H), 0.80-3.35 (m, 21H). ¹³C NMR (125 MHz, MeOD): δ 173.0,161.3 (d, J=242.1 Hz), 156.4, 151.4 (d, J=10.2 Hz), 139.8, 128.1, 127.8,124.9 (d, J=3.2 Hz), 123.7 (d, J=9.6 Hz), 116.6, 114.4, 107.3 (d, J=21.5Hz), 102.3 (d, J=26.8 Hz), 82.7, 78.0, 66.7 (2C), 59.1, 54.1 (2C), 51.2,50.4, 44.1, 40.8, 37.3, 36.1, 31.0, 30.4, 28.3, 25.8, 24.1, 24.0, 13.7.¹⁹F NMR (282 MHz, MeOD): δ −117.17. HR-MS (ESI) calcd for [C₃₃H₄₃FN₂O₅H]⁺ 567.3234, found 567.3226.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-(dimethylamino)-pentanamide

¹H NMR (500 MHz, CDCl₃): δ 8.08 (dd, J=8.9, 6.3 Hz, 1H), 7.10-7.50 (m,10H), 6.78 (m, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.63 (td, J=8.6, 2.4 Hz,1H), 6.57 (dd, J=8.6, 2.3 Hz, 1H), 5.04 (m, 1H), 4.97 (d, J=11.5 Hz,1H), 4.95 (d, J=11.5 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 4.49 (d, J=12.2Hz, 1H), 3.52 (dd, J=8.1, 8.1 Hz, 1H), 2.52 (s, 6H), 0.98 (s, 3H),0.80-3.00 (m, 21H). ¹³C NMR (125 MHz, CDCl₃): δ 169.5, 159.0 (d, J=241.2Hz), 156.7, 148.5 (d, J=9.9 Hz), 138.91, 138.85, 136.9, 128.6 (2C),128.3 (2C), 128.1, 128.0, 127.50 (2C), 127.48, 127.4 (2C), 126.4, 124.2(d, J=3.0 Hz), 120.5 (d, J=9.3 Hz), 115.7, 112.2, 107.0 (d, J=22.0 Hz),100.9 (d, J=27.1 Hz), 88.3, 77.3, 71.7, 69.8, 57.7, 50.1, 49.3, 43.1(2C), 43.0, 41.0, 36.1, 34.5, 29.9, 27.6, 26.8, 24.4, 23.0, 22.2, 13.9.¹⁹F NMR (282 MHz, CDCl₃): δ −116.36. HR-MS (ESI) calcd for [C₄₅H₅₃FN₂O₄H]⁺ 705.4067, found 705.4076.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-(dimethylamino)pentan-amide,JD142

¹H NMR (500 MHz, MeOD): δ 7.80 (dd, J=8.9, 6.3 Hz, 1H), 7.02 (dd,J=10.6, 2.6 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.63 (td, J=8.6, 2.6 Hz,1H), 6.59 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.5, 2.5 Hz, 1H), 5.25 (m, 1H),3.71 (dd, J=8.3, 8.3 Hz, 1H), 2.84 (s, 6H), 0.87 (s, 3H), 0.80-3.40 (m,21H). ¹³C NMR (125 MHz, MeOD): δ 172.6, 161.4 (d, J=240.7 Hz), 156.3,151.5 (d, J=10.1 Hz), 139.9, 128.3, 127.8, 124.8 (d, J=3.1 Hz), 123.9(d, J=9.8 Hz), 116.6, 114.3, 107.3 (d, J=21.4 Hz), 102.3 (d, J=27.3 Hz),82.7, 78.1, 58.6, 51.3, 50.4, 44.1, 43.5 (2C), 40.8, 36.6, 36.1, 31.0,30.4, 28.3, 25.2, 24.0, 23.1, 13.7. ¹⁹F NMR (282 MHz, MeOD): δ −117.17.HR-MS (ESI) calcd for [C₃₁H₄₁FN₂O₄H]⁺ 525.3129, found 525.3121.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-(pyrrolidin-1-yl)-pentanamide

¹H NMR (500 MHz, CDCl₃): δ 8.06 (dd, J=9.0, 6.3 Hz, 1H), 7.20-7.45 (m,10H), 6.78 (d, J=2.5 Hz, 1H), 6.76 (s, 1H), 6.75 (d, J=2.6 Hz, 1H), 6.73(d, J=8.7 Hz, 1H), 6.61 (td, J=8.6, 2.6 Hz, 1H), 6.55 (dd, J=8.6, 2.6Hz, 1H), 5.02 (m, 1H), 4.98 (d, J=11.5 Hz, 1H), 4.95 (d, J=11.5 Hz, 1H),4.58 (d, J=12.2 Hz, 1H), 4.47 (d, J=12.2 Hz, 1H), 3.50 (dd, J=8.1, 8.1Hz, 1H), 2.81 (m, 4H), 1.76 (m, 4H), 0.97 (s, 3H), 0.80-3.30 (m, 21H).¹³C NMR (125 MHz, CDCl₃): δ 169.4, 158.9 (d, J=245.0 Hz), 156.6, 148.4(d, J=10.1 Hz), 138.83, 138.81, 136.8, 128.4 (2C), 128.2 (2C), 128.1,127.9, 127.4 (2C), 127.34, 127.27 (2C), 126.3, 124.0 (d, J=3.2 Hz),120.4 (d, J=9.3 Hz), 115.6, 112.0, 106.8 (d, J=22.1 Hz), 100.8 (d,J=26.9 Hz), 88.2, 77.3, 71.5, 69.7, 54.9, 53.2 (2C), 50.0, 49.2, 42.9,40.9, 35.9, 34.3, 29.8, 27.5, 26.6, 25.0, 23.1 (2C), 22.8, 22.1, 13.8.¹⁹F NMR (282 MHz, CDCl₃): δ −116.29. HR-MS (ESI) calcd for [C₄₇H₅₅FN₂O₄H]⁺ 731.4224, found 731.4247.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-fluorophenyl)-5-(pyrrolidin-1-yl)pentan-amide,JD143

¹H NMR (500 MHz, MeOD): δ 7.81 (dd, J=8.9, 6.3 Hz, 1H), 7.01 (dd,J=10.6, 2.5 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.63 (dt, J=8.4, 2.8 Hz,1H), 6.60 (d, J=2.3 Hz, 1H), 6.40 (dd, J=8.5, 2.4 Hz, 1H), 5.22 (m, 1H),3.71 (dd, J=8.2, 8.2 Hz, 1H), 2.57 (m, 4H), 1.65 (m, 4H), 0.86 (s, 3H),0.75-3.50 (m, 21H). ¹³C NMR (125 MHz, MeOD): δ 172.6, 161.3 (d, J=242.5Hz), 156.3, 151.5 (d, J=10.1 Hz), 139.9, 128.2, 127.8, 124.8 (d, J=3.3Hz), 123.8 (d, J=9.9 Hz), 116.6, 114.3, 107.3 (d, J=22.1 Hz), 102.3 (d,J=27.4 Hz), 82.6, 78.0, 55.7, 55.0 (2C), 51.2, 50.3, 44.1, 40.8, 36.7,36.0, 31.0, 30.4, 28.2, 26.5, 23.97 (2C), 23.95, 23.3, 13.7. ¹⁹F NMR(282 MHz, MeOD): δ −117.06. HR-MS (ESI) calcd for [C₃₃H₄₃FN₂O₄ H]⁺551.3285, found 551.3286.

(8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-11-(4-nitro-3-(trifluoromethyl)-phenoxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene

¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H), 7.25-7.50 (m, 11H),7.22 (d, J=2.4 Hz, 1H), 7.11 (dd, J=9.0, 2.5 Hz, 1H), 6.83 (d, J=8.6 Hz,1H), 6.76 (d, J=2.2 Hz, 1H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 5.38 (m, 1H),5.00 (s, 2H), 4.56 (d, J=12.2 Hz, 1H), 4.47 (d, J=12.2 Hz, 1H), 3.55 (d,J=7.5, 7.5 Hz, 1H), 0.96 (s, 3H), 0.80-3.20 (m, 13H). ¹³C NMR (75 MHz,CDCl₃): δ 161.1, 156.8, 140.4 (q, J=1.6 Hz), 138.9, 138.6, 137.1, 128.5(2C), 128.33, 128.25 (2C), 127.8, 127.7, 127.42, 127.37 (2C), 127.3(2C), 125.7, 124.9 (q, J=182.9 Hz), 120.0 (q, J=5.1 Hz), 116.9, 115.6(q, J=5.7 Hz), 115.3, 112.6, 88.2, 73.8, 71.6, 69.8, 50.5, 48.6, 43.0,39.1, 33.7, 29.7, 27.5, 27.2, 23.0, 13.9. ¹⁹F NMR (282 MHz, CDCl₃): δ−59.97.

4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)aniline

¹H NMR (300 MHz, CDCl₃): δ 7.20-7.50 (m, 10H), 7.00 (s, 1H), 6.98 (d,J=3.8 Hz, 1H), 6.89 (dd, J=8.7, 2.7 Hz, 1H), 6.74 (m, 2H), 6.67 (d,J=8.9 Hz, 1H), 5.13 (m, 1H), 5.01 (s, 2H), 4.55 (d, J=12.2 Hz, 1H), 4.50(d, J=12.2 Hz, 1H), 3.86 (br s, 2H), 3.50 (dd, J=7.9, 7.9 Hz, 1H), 1.05(s, 3H), 0.90-3.10 (m, 13H). ¹³C NMR (75 MHz, CDCl₃): δ 156.6, 149.9,140.4, 139.1, 138.5, 137.9 (q, J=1.8 Hz), 137.3, 128.7, 128.5 (2C),128.2 (2C), 127.8, 127.4 (2C), 127.3 (2C), 126.5, 122.7 (q, J=195.4 Hz),121.2, 120.6 (q, J=12.5 Hz), 118.8, 115.0, 113.1 (q, J=5.3 Hz), 112.5,88.5, 72.8, 71.5, 69.8, 50.9, 48.9, 43.1, 39.2, 33.7, 29.8, 27.7, 27.3,23.0, 13.8. ¹⁹F NMR (282 MHz, CDCl₃): δ −62.57. HR-MS (ESI) calcd for[C₃₉H₄₀F₃NO₃ H]⁺ 628.3038, found 628.3016.

(8S,9S,11S,13S,14S,17S)-11-(4-Amino-3-(trifluoromethyl)phenoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol,JD128

¹H NMR (300 MHz, MeOD): δ 6.90 (m, 3H), 6.79 (m, 1H), 6.49 (m, 2H), 5.17(m, 1H), 3.64 (dd, J=7.2, 7.2 Hz, 1H), 0.90 (s, 3H), 0.80-3.40 (m, 13H).¹³C NMR (75 MHz, MeOD): δ 155.8, 150.9, 140.3 (q, J=2.0 Hz), 139.6,128.7, 127.8, 123.1 (q, J=223.5 Hz), 122.5, 120.3, 118.1 (q, J=14.9 Hz),116.2, 113.9, 113.7 (q, J=5.7 Hz), 82.9, 74.4, 51.8, 50.2, 44.2, 39.3,35.6, 30.9, 30.5, 28.5, 23.9, 13.8. ¹⁹F NMR (282 MHz, MeOD): δ −64.06.HR-MS (ESI) calcd for [C₂₅H₂₈F₃NO₃ H]⁺ 448.2100, found 448.2087.

(8S,9S,11S,13S,14S,17S)-13-Methyl-11-(4-nitro-3-(trifluoromethyl)phenoxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol,JD146

¹H NMR (500 MHz, MeOD): δ 8.05 (d, J=9.0 Hz, 1H), 7.32 (dd, J=9.1, 2.6Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.50 (d, J=2.5Hz, 1H), 6.41 (dd, J=8.5, 2.6 Hz, 1H), 5.54 (m, 1H), 3.68 (dd, J=8.3,8.3 Hz, 1H), 2.60 (d, J=11.1 Hz, 1H), 2.44 (dd, J=14.5, 2.4 Hz, 1H),0.84 (s, 3H), 0.80-3.50 (m, 11H). ¹³C NMR (125 MHz, MeOD): δ 162.7,156.0, 141.6, 139.7, 129.5, 127.9, 127.2, 126.7 (q, J=35.4 Hz), 123.4(q, J=272.8 Hz), 118.8, 116.41, 116.37 (q, J=6.0 Hz), 114.0, 82.6, 75.5,54.7, 51.4, 44.1, 39.2, 35.5, 30.7, 30.4, 28.3, 23.9, 13.8. ¹⁹F NMR (282MHz, MeOD): δ −61.45. HR-MS (ESI) calcd for [C₂₅H₂₆F₃NO₅ H]⁺ 478.1841,found 478.1840.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-morpho-linoacetamide

¹H NMR (300 MHz, CDCl₃): δ 9.65 (s, 1H), 8.19 (d, J=9.2 Hz, 1H),7.20-7.41 (m, 11H), 7.07 (s, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.5Hz, 1H), 6.65 (dd, J=8.6, 2.6 Hz, 1H), 5.24 (m, 1H), 4.98 (s, 2H), 4.52(d, J=12.3 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 3.77 (t, J=4.2 Hz, 4H),2.62 (t, J=4.2 Hz, 4H), 0.98 (s, 3H), 0.80-3.70 (m, 16H). ¹³C NMR (75MHz, CDCl₃): δ 168.4, 156.6, 154.0, 139.0, 138.5, 137.2, 128.4 (2C),128.3, 128.2 (2C), 127.8, 127.5, 127.4 (2C), 127.31, 127.3 (2C), 126.2,125.1, 121.3 (q, J=274.6 Hz), 120.7 (q, J=40.7 Hz), 118.5, 115.0, 113.5(q, J=4.0 Hz), 112.5, 88.3, 72.3, 71.5, 69.8, 66.9 (2C), 62.1, 53.7(2C), 50.7, 48.7, 43.0, 39.0, 33.7, 29.6, 27.6, 27.3, 23.0, 13.7. ¹⁹FNMR (282 MHz, CDCl₃): δ −60.70. HR-MS (ESI) calcd for [C₄₅H₄₉F₃N₂O₅ H]⁺755.3672, found 755.3695.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-morpholino-acetamide,JD144

¹H NMR (300 MHz, MeOD): δ 7.85 (d, J=8.8 Hz, 1H), 7.18 (dd, J=9.0, 2.6Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.49 (d, J=2.4Hz, 1H), 6.40 (dd, J=8.5, 2.5 Hz, 1H), 5.39 (m, 1H), 3.74 (t, J=4.2 Hz,4H), 3.67 (dd, J=8.3, 8.3 Hz, 1H), 2.61 (m, 4H), 0.87 (s, 3H), 0.80-3.32(m, 15H). ¹³C NMR (75 MHz, MeOD): δ 171.6, 156.8, 156.0, 139.6, 128.9,128.4, 128.04 (q, J=1.0 Hz), 127.5, 124.6 (q, J=29.9 Hz), 121.9 (q,J=226.6 Hz), 120.1, 116.3, 114.2 (q, J=5.7 Hz), 114.0, 82.8, 74.2, 68.0(2C), 62.8, 54.8 (2C), 51.7, 50.0, 44.2, 39.2, 35.6, 30.8, 30.5, 28.5,23.9, 13.8. ¹⁹F NMR (282 MHz, MeOD): δ −62.32. HR-MS (ESI) calcd for[C₃₁H₃₇F₃N₂O₅ H]⁺ 575.2733, found 575.2729.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-(piper-idin-1-yl)acetamide

¹H NMR (300 MHz, CDCl₃): δ 9.76 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.64(dd, J=5.7, 3.3 Hz, 1H), 7.46 (dd, J=5.7, 3.3 Hz, 1H), 7.10-7.40 (m,9H), 6.99 (s, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 6.58(d, J=8.5 Hz, 1H), 5.18 (m, 1H), 4.91 (s, 2H), 4.45 (d, J=12.2 Hz, 1H),4.39 (d, J=12.2 Hz, 1H), 2.50 (m, 4H), 1.58 (m, 4H), 0.90 (s, 3H),0.75-3.50 (m, 18H). ¹³C NMR (75 MHz, CDCl₃): δ 167.5, 156.4, 153.7,138.8, 138.3, 137.0, 132.2, 130.7, 128.6, 128.3 (2C), 128.2, 128.0 (2C),127.6, 127.2 (2C), 127. 1 (2C), 126.05, 121.5 (q, J=273.0 Hz), 121.3 (q,J=65.7 Hz), 118.2, 114.8, 112.9 (q, J=61.1 Hz), 112.3, 88.2, 72.1, 71.3,69.6, 67.9, 54.7 (2C), 48.5, 42.8, 40.5, 38.8, 38.5, 33.5, 29.4, 28.7,25.8 (2C), 23.5, 22.7, 13.5. ¹⁹F NMR (282 MHz, MeOD): δ −61.14. HR-MS(ESI) calcd for [C₄₆H₅₁F₃N₂O₄ H]⁺ 753.3879, found 753.3917.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-(piperidin-1-yl)acetamide,JD145

¹H NMR (300 MHz, MeOD): δ 7.83 (d, J=8.7 Hz, 1H), 7.18 (d, J=9.0 Hz,1H), 7.13 (d, J=3.1 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.49 (d, J=2.4 Hz,1H), 6.42 (d, J=8.2 Hz, 1H), 5.40 (m, 1H), 3.67 (dd, J=7.2, 7.2 Hz, 1H),2.67 (m, 4H), 1.69 (m, 4H), 0.87 (s, 3H), 0.75-3.40 (m, 17H). ¹³C NMR(75 MHz, MeOD): δ 171.3, 156.8, 156.0, 139.6, 129.0, 128.4, 127.9 127.5,125.1 (q, J=272.4 Hz), 124.8 (q, J=29.9 Hz), 120.1, 116.3, 114.1 (q,J=5.5 Hz), 114.0, 82.8, 74.2, 62.6, 55.8 (2C), 51.7, 50.0, 44.2, 39.2,35.6, 30.8, 30.5, 28.5, 26.7 (2C), 24.4, 24.0, 13.8. ¹⁹F NMR (282 MHz,MeOD): δ −62.47. HR-MS (ESI) calcd for [C₃₂H₃₉F₃N₂O₄ H]⁺ 573.2940, found573.2942.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-(pyrro-lidin-1-yl)acetamide

¹H NMR (300 MHz, CDCl₃): δ 9.76 (s, 1H), 8.22 (t, J=10.3 Hz, 1H), 7.71(m, 1H), 7.53 (m, 1H), 7.10-7.40 (m, 8H), 7.06 (s, 1H), 6.91 (d, J=8.8Hz, 1H), 6.72 (m, 2H), 6.66 (d, J=8.7 Hz, 1H), 5.24 (m, 1H), 4.99 (s,2H), 4.52 (d, J=12.1 Hz, 1H), 4.47 (d, J=12.1 Hz, 1H), 2.72 (m, 4H),1.60 (m, 4H), 0.98 (s, 3H), 0.80-4.30 (m, 16H). ¹³C NMR (75 MHz, CDCl₃):δ 167.7, 156.7, 153.9, 139.0, 138.5, 137.2, 132.4, 130.8, 128.8, 128.5(2C), 128.2 (2C), 127.8, 127.4 (2C), 127.3 (2C), 126.2, 125.1, 124.6 (q,J=274.9 Hz), 118.4, 117.9 (q, J=7.9 Hz), 115.1, 113.6 (q, J=4.3 Hz),112.5, 88.4, 72.3, 71.5, 69.8, 68.1, 54.3 (2C), 50.7, 48.7, 43.0, 39.1,38.7, 30.3, 29.7, 28.9, 24.0 (2C), 22.9, 14.0. ¹⁹F NMR (282 MHz, CDCl₃):δ −61.20. HR-MS (ESI) calcd for [C₄₅H₄₉F₃N₂O₄ H]⁺ 739.3723, found739.3746.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-(pyrrolidin-1-yl)acetamide,JD147

¹H NMR (500 MHz, MeOD): δ 7.70 (d, J=8.9 Hz, 1H), 7.19 (dd, J=8.9, 2.7Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.49 (d, J=2.4Hz, 1H), 6.41 (dd, J=8.5, 2.6 Hz, 1H), 5.42 (m, 1H), 3.67 (dd, J=8.3,8.3 Hz, 1H), 2.89 (m, 4H), 1.92 (m, 4H), 0.86 (s, 3H), 0.80-3.60 (m,15H). ¹³C NMR (125 MHz, MeOD): δ 171.1, 157.2, 155.9, 139.6, 130.1,128.4, 127.7, 127.5, 126.0 (q, J=30.3 Hz), 125.0 (q, J=272.3 Hz), 120.1,116.3, 114.2 (q, J=5.4 Hz), 114.0, 82.8, 74.1, 59.1, 55.4 (2C), 51.6,50.0, 44.2, 39.2, 35.6, 30.8, 30.4, 28.5, 24.7 (2C), 23.9, 13.8. ¹⁹F NMR(282 MHz, MeOD): δ −62.61. HR-MS (ESI) calcd for [C₃₁H₃₇F₃N₂O₄ H]⁺559.2784, found 559.2797.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-(dimeth-ylamino)acetamide

¹H NMR (300 MHz, CDCl₃): δ 9.62 (s, 1H), 8.14 (d, J=9.6 Hz, 1H),7.10-7.50 (m, 9H), 7.07 (s, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.72 (m, 2H),6.67 (d, J=8.5 Hz, 2H), 5.24 (m, 1H), 4.99 (s, 2H), 4.53 (d, J=12.2 Hz,1H), 4.48 (d, J=12.2 Hz, 1H), 3.48 (dd, J=8.3, 8.3 Hz, 1H), 2.40 (s,6H), 0.99 (s, 3H), 0.75-3.40 (m, 15H). ¹³C NMR (75 MHz, CDCl₃): δ 169.3,156.7, 154.1, 139.0, 138.5, 137.2, 128.5 (2C), 128.4, 128.2 (2C), 128.1,127.8, 127.7, 127.4 (2C), 127.3 (2C), 126.2, 125.5, 123.1 (q, J=250.0Hz), 121.6 (q, J=28.3 Hz), 118.4, 115.1, 113.6 (q, J=5.6 Hz), 112.5,88.4, 72.3, 71.5, 69.8, 63.3, 50.8, 48.7, 45.8 (2C), 43.0, 39.1, 33.7,29.7, 27.6, 27.3, 23.0, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −61.15. HR-MS(ESI) calcd for [C₄₃H₄₇F₃N₂O₄ H]⁺ 713.3566, found 713.3575.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-2-(dimethylam-ino)acetamide,JD148

¹H NMR (500 MHz, MeOD): δ 7.67 (d, J=8.9 Hz, 1H), 7.19 (dd, J=8.9, 2.7Hz, 1H), 7.14 (d, J=2.8 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.49 (d, J=2.4Hz, 1H), 6.41 (dd, J=8.5, 2.5 Hz, 1H), 5.41 (m, 1H), 3.67 (dd, J=8.2,8.2 Hz, 1H), 2.48 (s, 6H), 0.86 (s, 3H), 0.78-3.50 (m, 15H). ¹³C NMR(125 MHz, MeOD): δ 171.3, 157.3, 155.9, 139.6, 130.4, 128.4, 127.7,127.5, 126.2 (q, J=30.4 Hz), 124.9 (q, J=271.4 Hz), 120.0, 116.3, 114.2(q, J=5.5 Hz), 114.0, 82.8, 74.1, 63.1, 51.6, 50.0, 45.8 (2C), 44.2,39.1, 35.6, 30.8, 30.4, 28.5, 23.9, 13.8. ¹⁹F NMR (282 MHz, MeOD): δ−62.60. HR-MS (ESI) calcd for [C₂₉H₃₅F₃N₂O₄ H]⁺ 533.2627, found533.2650.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-(piper-idin-1-yl)propanamide

¹H NMR (500 MHz, CDCl₃): δ 10.60 (s, 1H), 7.71 (d, J=9.7 Hz, 1H),7.10-7.48 (m, 10H), 7.06 (s, 1H), 7.05 (dd, J=6.9, 3.1 Hz, 1H), 6.90 (d,J=8.6 Hz, 1H), 6.71 (d, J=2.5 Hz, 1H), 6.67 (dd, J=8.6, 2.6 Hz, 1H),5.24 (m, 1H), 4.98 (s, 2H), 4.53 (d, J=12.3 Hz, 1H), 4.46 (d, J=12.3 Hz,1H), 3.47 (d, J=6.5, 6.5 Hz, 1H), 2.48 (m, 4H), 1.60 (m, 4H), 0.97 (s,3H), 0.80-3.30 (m, 19H). ¹³C NMR (125 MHz, CDCl₃): δ 171.7, 156.5,154.5, 138.9, 138.4, 137.1, 129.0, 128.4 (2C), 128.3, 128.2 (2C), 127.7,127.4 (2C), 127.28 (2C), 127.27, 126.2, 124.1 (q, J=29.6 Hz), 123.4 (q,J=273.6 Hz), 119.2 (q, J=20.8 Hz), 117.9, 115.0, 113.2 (q, J=5.4 Hz),112.5, 88.2, 71.9, 71.4, 69.7, 54.3, 53.8 (2C), 50.6, 48.6, 46.7, 42.9,40.5, 38.9, 33.6, 32.1, 29.6, 26.5, 25.1 (2C), 24.6, 13.6. ¹⁹F NMR (282MHz, CDCl₃): δ −60.92. HR-MS (ESI) calcd for [C₄₇H₅₃F₃N₂O₄ H]⁺ 767.4036,found 767.4003.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-(piperidin-1-yl)propanamide,JD149

¹H NMR (500 MHz, MeOD): δ 7.53 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.9 Hz,1H), 7.28 (d, J=2.1 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.65 (d, J=1.7 Hz,1H), 6.57 (dd, J=8.4, 2.0 Hz, 1H), 5.56 (m, 1H), 3.83 (dd, J=8.2, 8.2Hz, 1H), 2.98 (m, 4H), 1.92 (m, 4H), 1.01 (s, 3H), 0.90-3.60 (m, 19H).13C NMR (125 MHz, MeOD): δ 172.8, 157.9, 155.9, 139.6, 133.0, 128.4,128.5 (q, J=30.0 Hz), 127.5, 127.4, 124.8 (q, J=272.7 Hz), 119.9, 116.3,114.1 (q, J=4.6 Hz), 114.0, 82.7, 74.0, 54.6 (2C), 54.5, 51.6, 49.9,44.2, 39.1, 35.6, 31.8, 30.8, 30.4, 28.5, 25.1 (2C), 23.9, 23.6, 13.8.¹⁹F NMR (282 MHz, MeOD): δ −62.44. HR-MS (ESI) calcd for [C₃₃H₄₁F₃N₂O₄H]⁺ 587.3097, found 587.3116.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-morpho-linopropanamide

¹H NMR (500 MHz, CDCl₃): δ 10.27 (s, 1H), 7.80 (d, J=9.7 Hz, 1H),7.20-7.49 (m, 10H), 7.08 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 6.73 (d, J=2.6Hz, 1H), 6.67 (dd, J=8.6, 2.6 Hz, 1H), 5.26 (m, 1H), 4.99 (s, 2H), 4.54(d, J=12.3 Hz, 1H), 4.46 (d, J=12.2 Hz, 1H), 3.76 (m, 4H), 3.58 (dd,J=5.5, 5.5 Hz, 1H), 2.60 (m, 4H), 0.98 (s, 3H), 0.80-3.90 (m, 17H). ¹³CNMR (125 MHz, CDCl₃): δ 171.1, 156.6, 154.4, 138.9, 138.4, 137.1, 128.5,128.4 (2C), 128.3, 128.2 (2C), 128.1, 127.7, 127.4 (2C), 127.3 (2C),126.2, 123.6 (q, J=273.9 Hz), 123.5 (q, J=29.8 Hz), 119.3 (q, J=22.2Hz), 118.0, 115.0, 113.2 (q, J=4.8 Hz), 112.5, 88.2, 72.0, 71.4, 69.7,66.2 (2C), 54.3, 53.0 (2C), 50.6, 48.6, 42.9, 38.9, 33.6, 31.8, 29.6,27.5, 27.3, 23.0, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.71. HR-MS (ESI)calcd for [C₄₆H₅₁F₃N₂O₅ H]⁺ 769.3828, found 769.3804.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-morpholino-propanamide,JD152

¹H NMR (500 MHz, MeOD): δ 7.44 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.5, 2.1Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.50 (d, J=1.9Hz, 1H), 6.42 (dd, J=8.5, 2.2 Hz, 1H), 5.41 (m, 1H), 3.72 (t, J=4.2 Hz,4H), 3.68 (dd, J=8.4, 8.4 Hz, 1H), 2.62 (m, 4H), 0.87 (s, 3H), 0.80-3.50(m, 17H). ¹³C NMR (125 MHz, MeOD): δ 174.4, 157.6, 155.9, 139.6, 132.5,128.4, 127.8 (q, J=29.5 Hz), 127.7, 127.5, 124.9 (q, J=272.6 Hz), 119.9,116.3, 114.04 (q, J=2.5 Hz), 114.0, 82.7, 74.0, 67.5 (2C), 55.3, 54.2(2C), 51.6, 49.9, 44.2, 39.1, 35.6, 33.2, 30.8, 30.4, 28.5, 23.9, 13.8.¹⁹F NMR (282 MHz, MeOD): δ −62.30. HR-MS (ESI) calcd for [C₃₂H₃₉F₃N₂O₅H]⁺ 589.2889, found 589.2883.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-(pyrro-lidin-1-yl)propanamide

¹H NMR (500 MHz, CDCl₃): δ 10.96 (s, 1H), 7.90 (d, J=8.6 Hz, 1H),7.20-7.45 (m, 10H), 7.08 (d, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J=8.7Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.67 (dd, J=8.6, 2.5 Hz, 1H), 5.25 (m,1H), 4.99 (s, 2H), 4.54 (d, J=12.3 Hz, 1H), 4.47 (d, J=12.3 Hz, 1H),3.48 (dd, J=6.0, 6.0 Hz, 1H), 2.66 (m, 4H), 1.84 (m, 4H), 0.98 (s, 3H),0.80-3.50 (m, 17H). ¹³C NMR (125 MHz, CDCl₃): δ 171.4, 156.6, 154.1,139.0, 138.4, 137.2, 128.4 (2C), 128.3, 128.2 (2C), 127.8, 127.7, 127.4(2C), 127.28 (2C), 127.27, 126.2, 123.5 (q, J=273.7 Hz), 123.1 (q,J=29.9 Hz), 119.2 (q, J=21.6 Hz), 118.0, 115.0, 113.2 (q, J=5.4 Hz),112.5, 88.3, 72.0, 71.4, 69.7, 53.2 (2C), 51.4, 50.7, 48.6, 42.9, 38.9,34.3, 33.6, 29.7, 27.6, 27.3, 23.2 (2C), 23.0, 13.6. ¹⁹F NMR (282 MHz,CDCl₃): δ −61.58. HR-MS (ESI) calcd for [C₄₆H₅₁F₃N₂O₄ H]⁺ 753.3879,found 753.3881.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-(pyrrolidin-1-yl)propanamide,JD150

¹H NMR (500 MHz, MeOD): δ 7.43 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.8, 2.1Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.50 (d, J=1.9Hz, 1H), 6.42 (dd, J=8.4, 2.2 Hz, 1H), 5.40 (m, 1H), 3.67 (dd, J=8.2,8.2 Hz, 1H), 2.82 (t, J=6.7 Hz, 4H), 1.98 (m, 4H), 0.85 (s, 3H),0.80-3.40 (m, 17H). ¹³C NMR (125 MHz, MeOD): δ 172.6, 157.8, 155.9,139.6, 132.7, 128.4, 127.5, 128.12, 128.10 (q, J=15.8 Hz), 124.7 (q,J=276.1 Hz), 119.9, 116.3, 114.1 (q, J=5.3 Hz), 114.0, 82.7, 74.0, 55.0(2C), 52.1, 51.5, 49.8, 44.1, 39.1, 35.6, 33.5, 30.8, 30.4, 28.5, 24.1(2C), 23.9, 13.8. ¹⁹F NMR (282 MHz, MeOD): δ −62.51. HR-MS (ESI) calcdfor [C₃₂H₃₉F₃N₂O₄ H]⁺ 573.2940, found 573.2943.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-(dimeth-ylamino)propanamide

¹H NMR (500 MHz, CDCl₃): δ 11.22 (s, 1H), 7.97 (d, J=9.7 Hz, 1H),7.20-7.45 (m, 10H), 7.06 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.6Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 5.24 (m, 1H), 4.99 (s, 2H), 4.54(d, J=12.3 Hz, 1H), 4.47 (d, J=12.3 Hz, 1H), 3.48 (dd, J=8.1, 8.1 Hz,1H), 2.32 (s, 6H), 0.98 (s, 3H), 0.80-3.00 (m, 17H). ¹³C NMR (125 MHz,CDCl₃): δ 171.2, 156.6, 153.9, 139.0, 138.4, 137.2, 128.5 (2C), 128.4,128.2 (2C), 127.8, 127.4 (2C), 127.3 (2C), 127.28, 127.26, 126.2, 123.7(q, J=230.8 Hz), 122.5 (q, J=12.0 Hz), 119.2 (q, J=22.1 Hz), 118.0,115.0, 113.4 (q, J=5.1 Hz), 112.5, 88.3, 72.0, 71.5, 69.8, 54.5, 50.7,48.6, 44.1 (2C), 43.0, 39.0, 33.6, 33.0, 29.7, 27.6, 27.3, 23.0, 13.7.¹⁹F NMR (282 MHz, CDCl₃): δ −61.80. HR-MS (ESI) calcd for [C₄₄H₄₉F₃N₂O₄H]⁺ 727.3723, found 727.3730.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-3-(dimethylam-ino)propanamide,JD151

¹H NMR (500 MHz, MeOD): δ 7.47 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.8, 2.5Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.51 (d, J=2.3Hz, 1H), 6.42 (dd, J=8.5, 2.4 Hz, 1H), 5.42 (m, 1H), 3.68 (dd, J=8.2,8.2 Hz, 1H), 2.57 (s, 6H), 0.87 (s, 3H), 0.80-3.50 (m, 17H). ¹³C NMR(125 MHz, MeOD): δ 173.2, 157.7, 155.9, 139.6, 132.4, 128.4, 128.1 (q,J=29.7 Hz), 127.7, 127.5, 124.8 (q, J=273.4 Hz), 120.2, 116.3, 114.1 (q,J=5.2 Hz), 114.0, 82.7, 74.0, 55.4, 51.6, 49.9, 44.4 (2C), 44.2, 39.1,35.6, 32.7, 30.8, 30.4, 28.5, 23.9, 13.8. ¹⁹F NMR (282 MHz, MeOD): δ−62.65. HR-MS (ESI) calcd for [C₃₀H₃₇F₃N₂O₄ H]⁺ 547.2784, found547.2759.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-(piperi-din-1-yl)butanamide

¹H NMR (500 MHz, CDCl₃): δ 8.44 (s, 1H), 7.52 (d, J=8.7 Hz, 1H),7.20-7.40 (m, 10H), 7.05 (s, 1H), 7.02 (d, J=9.1 Hz, 1H), 6.85 (d, J=8.6Hz, 1H), 6.69 (s, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.22 (m, 1H), 4.96 (s,2H), 4.50 (d, J=12.2 Hz, 1H), 4.43 (d, J=12.3 Hz, 1H), 3.45 (dd, J=6.8,6.8 Hz, 1H), 2.65 (m, 4H), 1.58 (m, 4H), 0.94 (s, 3H), 0.80-3.30 (m,21H). ¹³C NMR (125 MHz, CDCl₃): δ 171.1, 156.5, 155.5, 138.9, 138.4,137.1, 129.9, 128.39 (2C), 128.2 (2C), 127.7, 127.35 (2C), 127.26 (2C),127.23, 126.6, 126.1, 125.6 (q, J=29.0 Hz), 123.3 (q, J=272.5 Hz),118.1, 115.0, 113.4 (q, J=5.4 Hz), 112.4, 88.2, 72.1, 71.4, 69.7, 56.4,53.3 (2C), 50.6, 48.5, 42.9, 38.9, 33.6, 33.1, 32.3, 29.6, 27.5, 22.9,22.7 (2C), 22.2, 19.8, 13.6. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.65. HR-MS(ESI) calcd for [C₄₈H₅₅F₃N₂O₄ H]⁺ 781.4192, found 781.4221.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-(piperidin-1-yl)butanamide,JD160

¹H NMR (500 MHz, MeOD): δ 7.31 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.8, 2.7Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.49 (d, J=2.5Hz, 1H), 6.41 (dd, J=8.5, 2.6 Hz, 1H), 5.42 (m, 1H), 3.67 (dd, J=8.3,8.3 Hz, 1H), 2.40 (m, 4H), 1.48 (m, 4H), 0.86 (s, 3H), 0.80-3.50 (m,21H). ¹³C NMR (125 MHz, MeOD): δ 175.6, 158.1, 155.9, 139.6, 133.3,129.1 (q, J=31.4 Hz), 128.4, 127.8, 127.5, 124.8 (q, J=270.6 Hz), 119.9,116.3, 114.2 (q, J=5.5 Hz), 114.0, 82.7, 74.1, 59.3, 55.3 (2C), 51.6,50.0, 44.2, 43.7, 39.1, 35.6, 34.8, 30.8, 28.5, 26.1 (2C), 24.8, 23.9,23.0, 13.8. ¹⁹F NMR (282 MHz, MeOD): δ −62.51. HR-MS (ESI) calcd for[C₃₄H₄₃F₃N₂O₄ H]⁺ 601.3253, found 601.3267.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-morpho-linobutanamide

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, J=9.6 Hz, 1H), 7.70 (s, 1H),7.20-7.50 (m, 10H), 7.06 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.5Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 5.25 (m, 1H), 4.99 (s, 2H), 4.54(d, J=12.3 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 3.70 (m, 4H), 3.48 (dd,J=8.2, 8.2 Hz, 1H), 2.45 (m, 4H), 0.97 (s, 3H), 0.80-3.80 (m, 19H). ¹³CNMR (125 MHz, CDCl₃): δ 171.5, 156.6, 154.7, 138.9, 138.5, 137.1, 128.5(2C), 128.2 (2C), 128.1, 127.8, 127.5, 127.4 (2C), 127.34, 127.32 (2C),127.1, 126.2, 123.6 (q, J=273.7 Hz), 123.3 (q, J=30.8 Hz), 118.3, 115.0,113.5 (q, J=5.5 Hz), 112.5, 88.2, 72.2, 71.5, 69.8, 66.8 (2C), 57.5,53.5 (2C), 50.7, 48.7, 43.0, 38.9, 35.0, 33.6, 29.7, 27.6, 27.3, 23.0,21.9, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.74. HR-MS (ESI) calcd for[C₄₇H₅₃F₃N₂O₅ H]⁺ 783.3985, found 783.3984.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-morpholino-butanamide,JD153

¹H NMR (500 MHz, MeOD): δ 7.32 (d, J=8.7 Hz, 1H), 7.18 (dd, J=8.7, 1.7Hz, 1H), 7.14 (s, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.49 (d, J=1.7 Hz, 1H),6.41 (dd, J=8.5, 2.1 Hz, 1H), 5.42 (m, 1H), 3.73 (t, J=4.3 Hz, 4H), 3.67(dd, J=8.2, 8.2 Hz, 1H), 2.64 (m, 4H), 0.86 (s, 3H), 0.80-3.40 (m, 19H).¹³C NMR (125 MHz, MeOD): δ 175.5, 158.0, 155.9, 139.6, 133.2, 129.0 (q,J=30.8 Hz), 128.4, 127.8, 127.5, 124.8 (q, J=273.1 Hz), 119.9, 116.3,114.2 (q, J=5.3 Hz), 114.0, 82.7, 74.1, 67.2 (2C), 59.0, 54.5 (2C),51.6, 49.9, 44.2, 39.1, 35.6, 34.5, 30.8, 30.4, 28.5, 23.9, 22.7, 13.8.¹⁹F NMR (282 MHz, MeOD): δ −62.47. HR-MS (ESI) calcd for [C₃₃H₄₁F₃N₂O₅H]⁺ 603.3046, found 603.3047.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-(pyrroli-din-1-yl)butanamide

¹H NMR (500 MHz, CDCl₃): δ 8.35 (s, 1H), 7.53 (d, J=8.7 Hz, 1H),7.20-7.40 (m, 10H), 7.06 (s, 1H), 7.04 (d, J=9.0 Hz, 1H), 6.85 (d, J=8.6Hz, 1H), 6.70 (s, 1H), 6.65 (d, J=8.6 Hz, 1H), 5.23 (m, 1H), 4.97 (s,2H), 4.52 (d, J=12.2 Hz, 1H), 4.44 (d, J=12.2 Hz, 1H), 0.95 (s, 3H),0.80-3.50 (m, 28H). ¹³C NMR (125 MHz, CDCl₃): δ 171.0, 156.6, 155.6,138.9, 138.4, 137.1, 130.0, 128.5, 128.4 (2C), 128.2 (2C), 127.8, 127.4(2C), 127.31 (2C), 127.29, 126.5, 126.1, 125.6 (q, J=27.6 Hz), 123.4 (q,J=274.1 Hz), 118.2, 115.0, 113.5 (q, J=5.3 Hz), 112.5, 88.2, 72.2, 71.5,69.8, 54.4, 53.7 (2C), 50.6, 48.6, 42.9, 38.9, 33.6, 32.8, 29.6, 27.6,27.3, 23.3 (2C), 23.0, 21.8, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.61.HR-MS (ESI) calcd for [C₄₇H₅₃F₃N₂O₄ H]⁺ 767.4036, found 767.4067.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-(pyrrolidin-1-yl)butanamide,JD154

¹H NMR (500 MHz, MeOD): δ 7.31 (d, J=8.7 Hz, 1H), 7.18 (dd, J=8.8, 2.3Hz, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.48 (d, J=2.0Hz, 1H), 6.40 (dd, J=8.5, 2.2 Hz, 1H), 5.42 (m, 1H), 3.67 (dd, J=8.2,8.2 Hz, 1H), 2.57 (m, 4H), 1.81 (m, 4H), 0.86 (s, 3H), 0.80-3.50 (m,19H). ¹³C NMR (125 MHz, MeOD): δ 175.7, 158.0, 156.4, 139.6, 133.2,129.0 (q, J=29.3 Hz), 128.1, 127.9, 127.5, 124.8 (q, J=272.2 Hz), 119.9,116.4, 114.2 (q, J=5.0 Hz), 114.16, 82.8, 74.1, 56.8, 55.0 (2C), 51.7,50.0, 44.2, 39.2, 35.7, 35.0, 30.8, 30.5, 28.6, 25.7, 24.2 (2C), 24.0,13.8. ¹⁹F NMR (282 MHz, MeOD): δ −62.53. HR-MS (ESI) calcd for[C₃₃H₄₁F₃N₂O₄ H]⁺ 587.3097, found 587.3122.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-(dimeth-ylamino)butanamide

¹H NMR (500 MHz, CDCl₃): δ 8.36 (s, 1H), 7.61 (d, J=8.7 Hz, 1H),7.20-7.40 (m, 10H), 7.07 (s, 1H), 7.05 (d, J=12.3 Hz, 1H), 6.87 (d,J=8.7 Hz, 1H), 6.71 (s, 1H), 6.67 (dd, J=8.6, 2.2 Hz, 1H), 5.24 (m, 1H),4.98 (s, 2H), 4.53 (d, J=12.3 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H), 3.47(dd, J=7.7, 7.7 Hz, 1H), 2.61 (s, 6H), 0.96 (s, 3H), 0.80-3.00 (m, 19H).¹³C NMR (125 MHz, CDCl₃): δ 171.1, 156.6, 155.3, 138.9, 138.4, 137.1,129.4, 128.5, 128.4 (2C), 128.2 (2C), 127.8, 127.4 (2C), 127.34, 127.3(2C), 126.7, 126.1, 125.0 (q, J=32.4 Hz), 123.4 (q, J=275.1 Hz), 118.2,115.0, 113.4 (q, J=5.0 Hz), 112.5, 88.2, 72.2, 71.4, 69.8, 57.4, 50.6,48.6, 43.5 (2C), 42.9, 38.9, 33.6, 33.5, 29.6, 27.5, 27.3, 23.0, 21.1,13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.68. HR-MS (ESI) calcd for[C₄₅H₅₁F₃N₂O₄H]⁺ 741.3879, found 741.3911.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-4-(dimethylam-ino)butanamide,JD155

¹H NMR (500 MHz, MeOD): δ 7.31 (d, J=8.7 Hz, 1H), 7.17 (dd, J=8.8, 2.6Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.48 (d, J=2.4Hz, 1H), 6.40 (dd, J=8.5, 2.6 Hz, 1H), 5.41 (m, 1H), 3.67 (dd, J=8.3,8.3 Hz, 1H), 2.25 (s, 6H), 0.86 (s, 3H), 0.80-3.40 (m, 19H). ¹³C NMR(125 MHz, MeOD): δ 175.6, 158.0, 156.4, 139.6, 133.2, 129.0 (q, J=29.9Hz), 128.1, 127.9, 127.5, 124.8 (q, J=273.0 Hz), 119.9, 116.5, 114.2 (q,J=5.2 Hz), 114.17, 82.8, 74.1, 59.9, 51.7, 50.0, 45.4 (2C), 44.2, 39.1,35.7, 34.8, 30.8, 30.5, 28.6, 24.3, 24.0, 13.8. ¹⁹F NMR (282 MHz, MeOD):δ −62.52. HR-MS (ESI) calcd for [C₃₁H₃₉F₃N₂O₄ H]⁺ 561.2940, found561.2912.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-(piperid-in-1-yl)pentanamide

¹H NMR (500 MHz, CDCl₃): δ 7.75 (d, J=9.5 Hz, 1H), 7.62 (s, 1H),7.20-7.40 (m, 10H), 7.05 (s, 1H), 7.04 (dd, J=7.4, 2.9 Hz, 1H), 6.87 (d,J=8.7 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 6.65 (dd, J=8.6, 2.3 Hz, 1H),5.85 (br.s, 1H), 5.23 (m, 1H), 4.97 (s, 2H), 4.52 (d, J=12.3 Hz, 1H),4.44 (d, J=12.2 Hz, 1H), 3.47 (dd, J=8.1, 8.1 Hz, 1H), 2.61 (m, 4H),1.48 (m, 4H), 0.96 (s, 3H), 0.80-3.00 (m, 23H). ¹³C NMR (125 MHz,CDCl₃): δ 171.5, 156.6, 154.8, 138.9, 138.4, 137.1, 128.43, 128.39 (2C),128.2, 128.15 (2C), 127.7, 127.34 (2C), 127.29, 127.26 (2C), 127.0,126.1, 123.8 (q, J=29.3 Hz), 123.5 (q, J=273.3 Hz), 118.2, 115.0, 113.4(q, J=5.1 Hz), 112.4, 88.2, 72.2, 71.4, 69.7, 57.9, 53.9 (2C), 50.6,48.6, 42.9, 38.9, 36.5, 33.8, 33.6, 29.6, 27.5, 27.2, 24.8, 24.4 (2C),23.4, 23.1, 13.6. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.75. HR-MS (ESI) calcdfor [C₄₉H₅₇F₃N₂O₄ H]⁺ 795.4349, found 795.4334.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-(piperidin-1-yl)pentanamide,JD156

¹H NMR (500 MHz, MeOD): δ 7.33 (d, J=8.7 Hz, 1H), 7.18 (d, J=8.8 Hz,1H), 7.13 (d, J=1.9 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.50 (s, 1H), 6.42(dd, J=8.4, 2.0 Hz, 1H), 5.40 (m, 1H), 3.67 (dd, J=8.2, 8.2 Hz, 1H),2.48 (t, J=7.6 Hz, 4H), 1.74 (t, J=7.6 Hz, 4H), 0.85 (s, 3H), 0.80-3.40(m, 23H). ¹³C NMR (125 MHz, MeOD): δ 175.3, 158.0, 155.9, 139.6, 133.4,129.0 (q, J=30.7 Hz), 128.4, 127.8, 127.5, 124.8 (q, J=271.6 Hz), 119.9,116.3, 114.2 (q, J=5.4 Hz), 114.0, 82.7, 74.0, 57.8, 54.2 (2C), 51.6,49.9, 44.2, 39.1, 35.9, 35.6, 30.8, 30.4, 28.5, 24.5, 24.2 (2C), 23.9,23.7, 22.8, 13.8. ¹⁹F NMR (376 MHz, MeOD): δ −62.96. HR-MS (ESI) calcdfor [C₃₅H₄₅F₃N₂O₄ H]⁺ 615.3409, found 615.3400.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-morpho-linopentanamide

¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, J=9.6 Hz, 1H), 7.35 (m, 11H), 7.07(d, J=2.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.67(dd, J=8.6, 2.6 Hz, 1H), 5.25 (m, 1H), 4.99 (s, 2H), 4.55 (d, J=12.3 Hz,1H), 4.46 (d, J=12.3 Hz, 1H), 3.73 (t, J=4.4 Hz, 4H), 3.49 (dd, J=8.1,8.1 Hz, 1H), 2.45 (m, 4H), 0.99 (s, 3H), 0.80-3.80 (m, 21H). ¹³C NMR(125 MHz, CDCl₃): δ 171.3, 156.6, 154.6, 138.9, 138.4, 137.1, 128.5,128.4 (2C), 128.21, 128.17 (2C), 127.7, 127.6, 127.35 (2C), 127.27 (2C),127.1, 126.1, 123.6 (q, J=273.4 Hz), 123.0 (q, J=29.7 Hz), 118.2, 115.0,113.4 (q, J=5.2 Hz), 112.5, 88.2, 72.2, 71.4, 69.7, 66.8 (2C), 58.4,53.6 (2C), 50.6, 48.6, 42.9, 38.9, 37.1, 33.6, 29.7, 27.5, 27.3, 25.8,23.3, 22.9, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ −60.73. HR-MS (ESI) calcdfor [C₄₈H₅₅F₃N₂O₅ H]⁺ 797.4141, found 797.4163.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-morpholino-pentanamide,JD157

¹H NMR (500 MHz, MeOD): δ 7.31 (d, J=8.7 Hz, 1H), 7.17 (dd, J=8.8, 2.6Hz, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.49 (d, J=2.4Hz, 1H), 6.41 (dd, J=8.5, 2.6 Hz, 1H), 5.40 (m, 1H), 3.72 (t, J=4.6 Hz,4H), 3.67 (dd, J=8.3, 8.3 Hz, 1H), 2.59 (m, 4H), 0.86 (s, 3H), 0.80-3.50(m, 21H). ¹³C NMR (125 MHz, MeOD): δ 175.9, 158.0, 155.9, 139.6, 133.3,129.0 (q, J=29.7 Hz), 128.4, 127.9, 127.5, 124.8 (q, J=272.4 Hz), 119.9,116.3, 114.2 (q, J=6.7 Hz), 114.0, 82.7, 74.0, 67.2 (2C), 59.4, 54.5(2C), 51.6, 49.9, 44.2, 39.1, 36.6, 35.6, 30.8, 30.4, 28.5, 26.2, 24.5,23.9, 13.8. ¹⁹F NMR (376 MHz, MeOD): δ −63.01. HR-MS (ESI) calcd for[C₃₄H₄₃F₃N₂O₅ H]⁺ 617.3203, found 617.3230.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-(pyrro-lidin-1-yl)pentanamide

¹H NMR (500 MHz, CDCl₃): δ 7.74 (s, 1H), 7.65 (d, J=8.6 Hz, 1H),7.20-7.40 (m, 10H), 7.05 (s, 1H), 7.043 (d, J=9.2 Hz, 1H), 6.87 (d,J=8.7 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.65 (dd, J=8.6, 2.3 Hz, 1H),5.23 (m, 1H), 4.97 (s, 2H), 4.52 (d, J=12.3 Hz, 1H), 4.44 (d, J=12.2 Hz,1H), 3.47 (dd, J=8.4, 8.4 Hz, 1H), 2.48 (m, 4H), 1.25 (m, 4H), 0.95 (s,3H), 0.80-3.40 (m, 21H). ¹³C NMR (125 MHz, CDCl₃): δ 171.3, 156.6,155.2, 138.9, 138.4, 137.2, 129.1, 128.49, 128.45 (2C), 128.23, 128.21(2C), 127.8, 127.41 (2C), 127.36, 127.32 (2C), 126.7, 126.2, 123.5 (q,J=274.5 Hz), 118.2, 115.0, 113.4 (q, J=5.5 Hz), 112.5, 88.3, 72.2, 71.5,69.8, 54.7, 53.4 (2C), 50.6, 48.6, 43.0, 38.9, 35.7, 33.6, 29.7, 27.6,27.3, 25.0, 23.2 (2C), 23.0, 22.3, 13.7. ¹⁹F NMR (282 MHz, CDCl₃): δ−60.75. HR-MS (ESI) calcd for [C₄₈H₅₅F₃N₂O₄ H]⁺ 781.4192, found781.4170.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-(pyrrolidin-1-yl)pentanamide,JD158

¹H NMR (500 MHz, MeOD): δ 7.33 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.8, 2.7Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.50 (d, J=2.4Hz, 1H), 6.41 (dd, J=8.5, 2.6 Hz, 1H), 5.41 (m, 1H), 3.67 (dd, J=8.1,8.1 Hz, 1H), 2.48 (t, J=6.9 Hz, 4H), 2.07 (m, 4H), 0.86 (s, 3H),0.80-3.50 (m, 21H). ¹³C NMR (125 MHz, MeOD): δ 175.4, 158.1, 155.9,139.6, 133.4, 129.1 (q, J=30.3 Hz), 128.4, 127.8, 127.5, 124.8 (q,J=272.5 Hz), 119.9, 116.3, 114.2 (q, J=5.1 Hz), 114.0, 82.7, 74.1, 55.8,55.0 (2C), 51.6, 49.9, 44.2, 39.1, 35.9, 35.6, 30.8, 30.4, 28.5, 26.4,24.0 (2C), 23.9, 23.5, 13.8. ¹⁹F NMR (376 MHz, MeOD): δ −63.01. HR-MS(ESI) calcd for [C₃₄H₄₃F₃N₂O₄ H]⁺ 601.3253, found 601.3257.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-bis(Benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-(dimeth-ylamino)pentanamide

¹H NMR (500 MHz, CDCl₃): δ 7.74 (d, J=9.6 Hz, 1H), 7.57 (s, 1H),7.20-7.40 (m, 10H), 7.06 (s, 1H), 7.05 (dd, J=6.6, 3.1 Hz, 1H), 6.87 (d,J=8.7 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.6, 2.5 Hz, 1H),5.24 (m, 1H), 4.98 (s, 2H), 4.53 (d, J=12.3 Hz, 1H), 4.45 (d, J=12.3 Hz,1H), 3.47 (dd, J=8.1, 8.1 Hz, 1H), 2.55 (s, 6H), 0.96 (s, 3H), 0.80-3.00(m, 21H). ¹³C NMR (125 MHz, CDCl₃): δ 171.3, 156.6, 155.0, 139.0, 138.5,137.2, 128.52, 128.48 (2C), 128.3, 128.2 (2C), 128.1, 127.8, 127.4 (2C),127.35 (2C), 126.9, 126.2, 124.0 (q, J=30.4 Hz), 123.6 (q, J=273.4 Hz),118.3, 115.0, 113.5 (q, J=5.3 Hz), 112.5, 88.3, 72.3, 71.5, 69.8, 57.9,50.7, 48.7, 43.7 (2C), 43.0, 39.0, 36.2, 33.7, 29.7, 27.6, 27.3, 24.8,23.0, 22.6, 13.7. ¹⁹F NMR (376 MHz, CDCl₃): δ −61.39. HR-MS (ESI) calcdfor [C₄₆H₅₃F₃N₂O₄ H]⁺ 755.4036, found 755.4004.

N-(4-(((8S,9S,11S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-deca-hydro-6H-cyclopenta[a]phenanthren-11-yl)oxy)-2-(trifluoromethyl)phenyl)-5-(dimethylam-ino)pentanamide,JD159

¹H NMR (500 MHz, MeOD): δ 7.31 (d, J=8.7 Hz, 1H), 7.17 (dd, J=8.8, 2.6Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.49 (d, J=2.3Hz, 1H), 6.41 (dd, J=8.5, 2.5 Hz, 1H), 5.41 (m, 1H), 3.67 (dd, J=8.3,8.3 Hz, 1H), 2.35 (s, 6H), 0.86 (s, 3H), 0.80-3.50 (m, 21H). ¹³C NMR(125 MHz, MeOD): δ 175.8, 158.0, 156.0, 139.6, 133.3, 129.0 (q, J=30.2Hz), 128.3, 127.9, 127.5, 124.8 (q, J=274.7 Hz), 119.9, 116.3, 114.2 (q,J=5.2 Hz), 114.0, 82.7, 74.1, 60.0, 51.6, 49.9, 45.0 (2C), 44.2, 39.1,36.6, 35.6, 30.8, 30.4, 28.5, 27.2, 24.4, 23.9, 13.8. ¹⁹F NMR (376 MHz,MeOD): δ −63.08. HR-MS (ESI) calcd for [C₃₂H₄₁F₃N₂O₄ H]⁺ 575.3097, found575.3123.

2. Compound Functional Characterization

For the biological testing alternative code names for the compounds wereused, namely JD101-JD160. The correspondence of the compound numbers inthe design and synthesis and the code names for functionalcharacterization are given in Table 1.

TABLE 1 Correspondence of the Novel ER Antagonists Chemical names andtheir alternative Code Names for Functional Characterization. Cmpd Code 8a JD101  8b JD102  8c JD103  8d JD104  7 JD105 11c JD106 11a JD107 11bJD108 11d JD109 12c JD110 12b JD111 12a JD112 13c JD113 13b JD114 13aJD115 12d JD116 13d JD117 10 JD118 15 JD119 20, 16 JD120  9c JD121 17aJD122  9b JD123  9a JD124 17b JD125 17c JD126  9d JD127 22 JD128 17dJD129 18a JD130 14c JD131 18b JD132 18d JD133 18c JD134 19c JD135 14aJD136 19a JD137 19b JD138 19d JD139 20a JD140 20c JD141 20d JD142 20bJD143 23c JD144 23a JD145 21 JD146 23b JD147 23d JD148 24a JD149 24bJD150 24d JD151 24c JD152 25c JD153 25b JD154 25d JD155 26a JD156 26cJD157 26b JD158 26d JD159 25a JD160

Assays for Cell Proliferation.

In experiments to assess potential proliferative effects of novelestrogen receptor ligands, human breast cancer cells were grown inphenol red-free, estrogen-free media with 1% dextran-coatedcharcoal-treated (DCC)-fetal bovine serum (FBS) for 48 hrs (15,44), thentreated with either 1 μM or 50 μM doses of estrogen receptor antagonistsin the presence of 1 nM estradiol-17β. Cell counts and viability tests(Trypan blue) were done every 24 hr for 3 days. After 72 hr,proliferation was assessed using the BrdU Cell proliferation ELISA(Roche). Cell numbers were also assessed initially by cell counts toconfirm ELISA data. Each antiestrogen was tested at least in threedifferent experiments.

Gel Electrophoresis and Immunoblotting.

MCF-7 breast cancer cells were maintained in estrogen-free conditions 48h before experiments as described above. Cells were then incubated withvehicle control or either 1 μM or 10 μM antiestrogens in the presence of1 nM estradiol-17β for 48 hrs. After lysis, total cell proteins wereresolved by 4-15% SDS-PAGE, transferred to polyvinylidene difluoridemembranes and probed with mouse monoclonal antibody directed againstestrogen receptor-alpha (Assay Designs, #SRA1010). Membranes werestripped and re-probed with Ribosomal Protein L13A (Santa CruzBiotechnology, C11) as a loading control (45).

In order to assess the antitumor action of novel estrogen receptorantagonists, we cultured human MCF-7 breast cancer cells with knownexpression of ERα. Cells were grown in 1% DCC-FBS for 48 hr and thentreated with vehicle control or either 1 μM or 50 μM concentrations ofantiestrogens JD 101-160 or the pure antiestrogen fulvestrant (FAS), allin the presence of 1 nM estradiol-17β. The results indicate that severalnovel antiestrogens exert significant inhibition of MCF-7 cellproliferation/survival, particularly JD128 and JD140. Moreover, thesecompounds appear to be more effective than the ER-downregulatorfulvestrant when administered at the same doses in vitro. Shown in FIG.2 are results from MCF-7 cells grown in 1% DCC-FBS for 48 hr and thentreated with vehicle control, 1 nM estradiol-17β and either 1 μM or 50μM concentrations of antiestrogens JD 101-160 or the known pureantiestrogen fulvestrant (FAS) in the presence of 1 nM estradiol-17β.Cell proliferation is expressed as percentage of that determined in the1 nM estradiol-17β-treated control group. The graph shows the percentageof surviving cells relative to estradiol-treated controls, defined as100% survival (data represents at least 3 independent experiments).

Novel Antiestrogen Compounds can Act as ERα Downregulators.

Fulvestrant (Faslodex®) has been characterized as a selective ERαdownregulator and a pure anti-estrogen. Fulvestrant inhibits thetranscriptional response to estrogen stimulation and induces thedegradation of estrogen receptor proteins (46,47). This drug has beendemonstrated to be clinically effective in treating metastatic breastcancer and represents an important option to extend the window ofendocrine interventions before cytotoxic chemotherapy becomes the onlyother systemic treatment available for patients. One problem withfulvestrant is that the drug requires intramuscular injection and maynot achieve optimal antitumor effects due to the limited doses that canbe administered by this drug delivery method. Hence, we assessed some ofour new antiestrogen analogues to find if they, as fulvestrant, affectexpression of ERα protein levels in breast cancer cells. MCF-7 breastcancer cells with high expression of ERα protein were treated withestradiol-17β and either 1 μM or 10 μM concentrations of JD128 and JD140for 48 hours. FIG. 3 shows results of Western immunoblots of ERα proteinlevels after treatments. Compound JD128 showed the greatest effect atsuppressing estrogen receptor-alpha expression in MCF-7 breast cancercells. As shown in FIG. 3, estrogen receptor-alpha is down-regulated byantiestrogens. MCF-7 breast cancer cells were estrogen-deprived for 48hrs, then treated with 1 nM estradiol-17β (E2) or antiestrogens JD128(128) or JD140 (140) at 1 μM or 10 μM concentrations in the presence of1 nM estradiol-17β. After 48 hrs, PAGE and immunoblotting was performedwith antibody directed to anti-ERα (SRA1010) and anti-RPL13A for aloading control. Given that recent FES-PET studies show significantresidual ER availability in tumors during fulvestrant therapy in 38% ofpatients which was related to early cancer progression (48), novelantiestrogens described herein may prove more effective than fulvestrantin suppressing ERα.

3. ER Pathway Interactions and Drug Resistance

Breast tumors with ER and HER2 overexpression are an unresolved clinicalproblem and a major cause of endocrine-treatment failure and mortality.Early resistance to hormonal therapy, especially in HER-2-overexpressingtumors, is a significant issue in the clinic. Several studies indicatethat ER+/HER-2+ cancer is less responsive to tamoxifen andestrogen-deprivation therapies with AI's than tumors negative for ER andHER-2 expression, indicating that HER-2 overexpression elicits adominant phenotype. Overexpression or activation of HER-2 or related HERfamily receptors occurs in two-thirds of breast tumors, while HER-2overexpression occurs in about 25% of breast cancers (2,21). Blockade ofHER-2 with trastuzumab (Herceptin), a humanized monoclonal antibodytargeted to HER-2, has provided an important clinical tool to managepatients with tumors bearing HER-2 overexpression or amplification(45,46).

Growth factors (EGF, heregulin) and estrogens are known mitogens forbreast cancer, and activation of ER by growth factors in the absence ofestrogen is a phenomenon that may be critical in cancer (14,47-49). ERsignaling may mediate gene transcription by integrating signals fromgrowth factor-activated pathways as well as from E2 binding (33,50).There is increasing evidence that endocrine resistance is a consequenceof such bidirectional crosstalk between ER and EGFR/HER family signalingnetworks (6,9). ER is a phosphoprotein, with ER phosphorylationoccurring early in it's activation by ligand (14,28, 29,51,52). Severalstudies show that phosphorylation at serine and tyrosine residuescontribute to ER activation and, possibly, DNA binding (14,28, 52).Conversion of estrogen-sensitive to -resistant tumors after startingantiestrogen therapy (47) may be due, in part, to enhanced growth factorsignaling, a cell response to antiestrogen treatment that eventuallyresults in increased phosphorylation of ER and/or coactivators, such asAIB1 (28,33). Since these two receptors systems (ER and HER) have thecapacity to activate each other, it has been suggested that a rationaltreatment strategy would be the combined targeting of both receptors byuse of antihormone therapy with anti-HER-2 agents, such as trastuzumab(Herceptin).

Panels of human ER-positive breast tumor cells with endocrinesensitivity and resistance. For this work, a panel of MCF-7 human breastcancer cells (ATCC) with different properties was used. This panelincludes cell lines reported previously and include: a) MCF-7/CON:MCF-7parent breast tumor cells with ER expression; b) TAM-R: MCF-7 cells withacquired tamoxifen-resistance, c) MCF-7/ER−: MCF-7 cells with no ERexpression; no E2-induced activation of MAPK or cell growth; and d)ER-positive T47D and ZR75 breast cancer cells.

Properties of TAM-R cells: To develop TAM-R cells, MCF-7 breast cellswere cultivated in vitro in the presence of tamoxifen as reported before(72). In brief, MCF-7 cell monolayers were cultivated in phenol-red-freeRPMI medium containing 5% charcoal-stripped steroid-depleted (DCC)-fetalcalf serum, antibiotics, glutamine (200 mM), and 4-hydroxytamoxifen(1×10-7 M 4-OH-TAM). Cells were continuously exposed to this treatmentfor 12 months, during which time medium was replaced every 4 days, andcell cultures were passaged by trypsinization after 70% confluency wasreached. Initially, MCF-7 cell growth rates were reduced but, after 4months' exposure to the medium, cell growth gradually increased,indicating development of a cell line resistant to the growth-inhibitoryproperties of 4-OH-TAM. This cell line, termed TAM-resistant, wascultured for a further 8 months in medium containing 4-OH-TAM beforecharacterization studies. These cells were evaluated for expression ofEGFR, HER-2 and ERα (FIG. 2). The results show that TAM-resistant cellshave higher levels of HER-2 and EGFR as compared withtamoxifen-sensitive progenitor MCF-7 cells, while expression levels ofER remain essentially unchanged. This finding may have importantimplications for the design of future therapeutic interventions. FIG.4a-b . shows MCF-7 cells with acquired tamoxifen resistance showincreased expression of HER-1/EGFR and HER-2 receptors. FIG. 4a shows aWestern blot showing protein expression level of HER2, EGFR, ERα andactin loading control in MCF-7 cells that were tamoxifen-sensitive(left) versus those that were tamoxifen-resistant (right). ERβ3 was alsoassessed and was low to absent in both sensitive and resistant cells.FIG. 4b shows levels of HER-2, HER-1/EGFR and ERα receptors inMCF-7/TAM-R cells that were quantitated using established ELISA methods(73), with results based on 3 determinations. The average number ofreceptors/tamoxifen-resistant cell was calculated and expressed relativeto that of tamoxifen-sensitive MCF-7 cells.

Properties of MCF-7/TAM-R, MCF-7/ER− and parental cells: MCF-7/CON(parental) cells are tamoxifen-sensitive, while MCF-7/TAM-R andMCF-7/ER− cells are known to be tamoxifen-resistant (11,14-16). Exceptfor TAM-R (72) and MCF-7/ER− (16), cells are routinely cultured in RPMI1640 media with 10% heat-inactivated FBS. For E2-free conditions, mediumis changed 48 h before studies to phenol-red free RPMI 1640 with 1%dextran-coated, charcoal-treated (DCC) FBS. Levels of ERα and HER2 wereassessed by immunofluorescence microscopy in MCF-7/CON and other cells.MCF-7/CON cells express ERα but few HER2 receptors, while MCF-7/TAM-Rcells express both ER and HER2. ER and HER2 were detected by establishedimmunofluorescence microscopy methods with labeled antibodies to ERα andHER2 (14-16). TAM-R cells also show increased expression of HER2 byimmunofluorescence (72). In contrast, expression of ERα appears to berelatively stable among the several cell lines, with only modestly lessintensity of immunofluorescence in TAM-R cells as compared to theirpaired controls.

In previous studies to evaluate the role of activated HER-2 inantiestrogen resistance, estrogen-responsive, MCF-7 parental cells andpaired MCF-7 cells with HER2-overexpression cells were grown asxenografts in nude mice (14). Parent tumors were suppressed by tamoxifenand by fulvestrant, while MCF-7/HER-2 cells were insensitive totamoxifen but were partially sensitive to fulvestrant (14,74,75). Thisfinding correlates well with data from the clinic suggesting tamoxifenresistance in breast tumors with high levels of HER2 expression (42). Inthe clinic, HER2 overexpression also associates with low ER levels (76)and a PR-negative phenotype (43) in breast tumors. Similarly, in thelaboratory, overexpression of HER2 in breast cells elicits a modestreduction in ER transcripts and in estrogen binding capacity with nochange in steroid binding affinity, as assessed by specific binding of[³H]-estradiol in cells with and without HER2 overexpression (14,36,74).This modest downregulation of ER may account, in part, for reducedendocrine sensitivity of HER2-expressing tumors, but other mechanismsare clearly operative (9,11,14,76).

Specific estradiol binding: Specific estradiol-17β (E2) binding wasassessed in MCF-7 parental breast cancer cells as before (14-16).Briefly, cells were incubated with 2 nM [³H]estradiol-17β and varyingconcentrations (1 nM-10 μM) of new estrogen receptor downregulator (ERD)analogues. The efficiency of the binding of compounds was measured bythe loss of radioactivity of the [³H]estradiol-17β. A 100-fold molarexcess of unlabeled E2 was present with [3H]estradiol-17β in pairedsamples for determination of displaceable binding. ICI 182,780(fulvestrant, 1 nM -10 μM) was used as a control. As shown in FIG. 5,the ligand binding specificity of labeled estradiol-17β was suppressedeffectively by 10 μM of ERD compound S15 (JD105) compared to select testcompounds. FIG. 5 shows specific binding of [³H]estradiol-17β by MCF-7parental breast cancer cells is suppressed by our ERD compound S15 inthis series of analogues (15). MCF-7 cells were incubated with 2 nM[³H]estradiol-17β and antiestrogens (all at 10 μM concentration; numbersS1 to S15), with ICI 182,780 (ICI; fulvestrant) used as a control (n=3).Compounds S1-S14 show less activity in the assay above than compound S15(JD105) as shown in FIG. 5. Compounds S1-S14 are test compoundsdifferent from the exemplified compounds described herein.

ER down-regulation: To determine if selected compounds can down-regulateER protein, we treated cells for 24-48 hrs in vitro with candidatecompounds at varying doses. Then, cells were disrupted and prepared forPAGE and Western immunoblots using anti-ERα antibodies (see FIG. 6). Arepresentative experiment shows that a selected ERD at doses of >100 nMelicits reduced ER levels. Those ERDs with optimal activity indown-regulating ER were investigated further in the chemistry laboratoryto further refine and develop such agents. Downregulation of ER couldprove to be an important drug property to overcome endocrine resistancedue to ligand-independent ER signaling (47, 71). FIG. 6 shows ERD S15reduces ER protein levels in MCF-7 breast tumor cells. Westernimmunoblot analysis of ER (66 kD) after treatment of MCF-7 cells for 24hours with SERM S15 at various concentrations (10, 100 and 1000 nM), ICI182,780 (ICI; fulvestrant; 100 nM), tamoxifen (TM; 100 nM) or controlvehicle (CON).

ERD inhibition of phosphorylation of MAPK, at both extracellularsignal-regulated kinases ERK-1 (p44) and ERK-2 (p42) and downstreameffects. As illustrated in FIG. 1, signal transduction induced byestrogen contributes to breast tumor proliferation, a late event thatcorrelates with early activation of MAPK by estradiol in breast tumorcells (9,15,16). Thus, we measured estrogen-induced phosphorylation ofMAPK by established methods (9,15,16). Briefly, MCF-7 parental cellswere estrogen deprived for 48 hrs, then treated with 1 nM estradiol-17βin the presence of new compounds (10 nM-10 μM) to be tested forantagonist activity. After treatments, cell lysates were separated bySDS-PAGE followed by Western blot using a polyclonal antibody directedto phospho-p44/p42 MAP kinase (Thr202/Tyr204) (Cell Signaling).Immunodetection with antibody against total p44/p42 (Cell Signaling) wasdone as a control for gel loading. As shown in FIG. 7, ERD S15 inhibitsphosphorylation of MAPK, at both extracellular signal-regulated kinasesERK-1 (p44) and ERK-2 (p42). ERD S15 was as effective as fulvestrant ininhibiting the rapid estrogen-induced MAPK phosphorylation in breasttumor cells in vitro. FIG. 7 shows treatment of MCF-7 parent cells with1 nM estradiol 17β (E2) induces rapid phosphorylation of MAPK (pMAPK).E2 but not vehicle (CN) induced rapid phosphorylation of ERK-1 (p44) andERK-2 (p42). This activation was prevented when cells were pre-incubatedwith 1000 nM ICI 182,780 (ICI; Faslodex) or 1000 nM compound S15 in thepresence of estradiol (E2).

4. Assays for Antiestrogen Effects on Non-Small Cell Lung Cancer CellProliferation.

To assess potential antiproliferative effects of novel antiestrogenssuch as compounds JD128 and JD140 in non-small cell lung cancer, humannon-small cell lung cancer cells A549 were grown in RPMI 1640 mediumwith 10% fetal bovine serum (FBS), then treated with either 1 μM or 10μM doses of estrogen receptor antagonists JD128, JD140 or fulvestrant.Cell counts and viability tests (Trypan blue) were done every 24 hoursfor 3 days. After 72 hours, proliferation was assessed using theCellTiter 96™ AQ_(ueous) One Solution Cell Proliferation Assay (MTS)from Promega. Cell numbers were also assessed initially by cell countsto confirm ELISA data. Each antiestrogen was tested in at least in threeindependent experiments.

ER has a major role in controlling breast cancer growth. Antiestrogentamoxifen has been the most widely used hormone therapy, achieving a 39%reduction in breast cancer recurrence and 31% reduction in mortality inER-positive early breast cancer. Tamoxifen has important drawbacks: alimited period of activity before resistance develops; and undesirableside-effects in normal tissues such as uterus due to the activity as apartial agonist. As long as ER is present, growth may be stimulated byestrogen, partial agonists or estrogen-independent action. Introductionof aromatase inhibitors for postmenopausal patients, either initially orafter tamoxifen, has yielded better outcomes than tamoxifen. However, inpatients with advanced breast cancer, only about one third ofER-positive breast cancers respond to aromatase inhibitors, andresistance can evolve due to ER activation by ER hypersensitivity orligand-independent ER activation that occurs in breast cancers withactivated growth factor receptors such as HER2. Such data offered arationale to target both ER and HER2 in ER-positive/HER2-positive breastcancers to overcome endocrine resistance.

A prototype drug in this class, fulvestrant is a pure ER antagonist withno major agonist activity and with a unique mechanism of action, i.e.downregulation of ER, due in part to induced destabilization andhyper-ubiquitination of ER leading to growth inhibition. But,fulvestrant suffers from low bioavailability which presents a problem inthe clinic. In about 14% of metastatic ER-positive breast cancers frompatients with multiple prior endocrine therapies, there is emergingevidence for the acquisition of functionally-aberrant ESR1 with pointmutations. Although such mutated ESR1 variants continue to respond to ERantagonists such as fulvestrant, elevated doses appear to be required toachieve wild-type levels of inhibition. However, the poorbioavailability of fulvestrant (which may require multiple intramuscularinjections of significant volumes of drug) appears to limit optimal druglevels in vivo. Such data underscores the need to search for more potentselective estrogen receptor downregulators.

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Additional references 1. Hurvitz S, Pietras R (2008). Rationalmanagement of endocrine resistance in breast cancer: a compre-hensivereview of estrogen receptor biology, treatment options and futuredirection. Cancer 113:2385-97. 2. Early Breast Cancer Trialists'Collaborative Group (1998). Tamoxifen for early breast cancer: anoverview of the randomised trials. Lancet 351:1451-67. 3. Ali S, CoombesR (2002). Endocrine-responsive breast cancer and strategies forcombating resistance. Nature Rev Cancer 21: 101-113. 4. Prat A, BaselgaJ (2008). The role of hormonal therapy in the management of hormonalreceptor-positive breast cancer with co-expression of HER2. Nat ClinPract Oncol 5: 531-542. 5. Robertson J F, Lindemann J, Garnett S,Anderson E, Nicholson R I, Kuter I, Gee J M (2014). A Good Drug MadeBetter: The Fulvestrant Dose-Response Story. Clin Breast Cancer.14:381-3 89. 6. van Kruchten M, de Vries E, Glaudemans A et al.Measuring residual estrogen receptor availability during fulvestranttherapy in patients with metastatic breast cancer. Cancer Discov 2014:ii: CD-14-0697. 7. O'Brien J, Peterson T, Tong M et al. (2006).Estrogen-induced proliferation of uterine epithelial cells isindependent of ERα binding to classical estrogen response elements. JBiol Chem 281: 26683-92. 8. Pietras R J, Marquez-Garban D C (2007).Membrane-associated estrogen receptor signaling pathways in humancancers. Clin Cancer Res 13: 4672-4676. 9. Syed F, Fraser D, SpelsbergT, Rosen C, Krust A, Chambon P, Jameson J, Khosla S (2007). Effects ofloss of classical estrogen response element signaling on bone in malemice. Endocrinology 148:1902-10. 10. Early Breast Cancer Trialists'Collaborative Group (2005). Effects of chemotherapy and hormonal therapyfor early breast cancer on recurrence and 15-year survival: an overviewof the randomised trials. Lancet 365: 1687-1717. 11. Weinberg O, MarquezD and Pietras R (2005). New approaches to reverse resistance to hormonaltherapy in human breast cancer. Drug Resistance Updates 8:219-33. 12.The Breast International Group 1-98 Collaborative Group (2005) Acomparison of letrozole and tamoxifen in postmenopausal women with earlybreast cancer. N Engl J Med 353: 2747-2757. 13. ATAC Trialists' Group(2005). Results of the ATAC (Arimidex, Tamoxifen, Alone or inCombination) trial after completion of 5 years' adjuvant treatment forbreast cancer. Lancet 365: 60-62. 14. Massarweh S, Osborne C K,Creighton C et al. (2008). Tamoxifen resistance in breast tumors isdriven by growth factor receptor signaling with repression of classic ER genomic function. Cancer Res 68:826-33. 15. Ellis M J et al. (2006)Estrogen-independent proliferation is present in estrogen-receptorHER2-positive primary breast cancer after neoadjuvant letrozole. J ClinOncol 24: 3019-3025. 16. Johnston S, Pippen J Jr, Pivot X et al. (2009).Lapatinib combined with letrozole versus letrozole and placebo asfirst-line therapy for postmenopausal hormone receptor-positivemetastatic breast cancer. J Clin Oncol. 27:5538-46. 17. Kieser K J, KimD W, Carlson K E, Katzenellenbogen B S, Katzenellenbogen J A (2010).Characterization of the pharmacophore properties of novel selectiveestrogen receptor downregulators (SERDs). J Med Chem. 53:3320-9. PMCID:PMC2916745. 18. Fan M, Rickert E, Chen L, Aftab S, Nephew K, WeathermanR V (2007). Characterization of molecular and structural determinants ofselective E R downregulators. Breast Cancer Res Treat 103:37-44. 19.Wakeling A E, Dukes M, Bowler J (1991). A potent specific pureantiestrogen with clinical potential. Cancer Res 51:3867-73. 20.Wijayaratne, A. L. and McDonnell, D. P. (2001) the human estrogenreceptor-alpha is an ubiquitinated protein whose stability is affecteddifferentially by agonists, antagonists, and selective estrogen receptormodulators. J. Biol. Chem. 276, 35684-356892. 21. Robinson D R, Wu Y M,Vats P et al. (2013). Activating ESR1 mutations in hormone-resistantmetastatic breast cancer. Nat Genet 2013, 45:1446-1451.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

G. Embodiments Embodiment 1

A compound having the formula

R¹ is independently a hydrogen,halogen, —NR²R³, —CX^(a) ₃, —CN, —SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR²R³,—NHNR²R³, —ONR²R³, —NHC═(O)NHNR²R³, NHC═(O)NR²R³, —N(O)_(m1), —C(O)R⁹,—C(O)—OR⁹, —C(O)NR²R³, —OR¹⁰, —NR²SO₂R¹⁰, —NR²C═(O)R⁹, —NR²C(O)—OR⁹,—NR²OR⁹, —OCX^(a) ₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. L isindependently abond, —NR⁴—, —NR⁴C(O)—, —C(O)NR⁴—, —O—, —S—, —C(O)—, —S(O)—, —S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, substituted or unsubstituted heteroarylene; or a substituted orunsubstituted spirocyclic linker. R² is independently a hydrogen,halogen, —CX^(b) ₃, —CN, —SO₂Cl, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂,—ONR¹¹R¹², —NHC═(O)NHNH₂, —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX^(b) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R³ is independently a hydrogen,halogen, —CX^(c) ₃, —CN, —SO₂Cl, —SO₃R¹, —SO_(v3)NR¹⁵R¹⁶, —NHNH₂,—ONR¹⁵R¹⁶, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁵R¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶,—C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷,—NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX^(c) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R² and R³ substituents may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. R⁴ is independently a hydrogen,halogen, —CX^(d) ₃, —CN, —SO₂Cl, —SO_(n4)R²², —SO_(v4)NR¹⁹R²⁰, —NHNH₂,—ONR¹⁹R²⁰, —NHC═(O)NHNH₂, —NHC═(O)NR¹⁹R²⁰, —N(O)_(m4), —NR¹⁹R²⁰,—C(O)R²¹, —C(O)—OR²¹, —C(O)NR¹⁹R²⁰, —OR²², —NR¹⁹SO₂R²², —NR¹⁹C═(O)R²¹,—NR¹⁹C(O)—OR²¹, —NR¹⁹OR²¹, —OCX^(d) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰,R²¹, and R²² are independently hydrogen,halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹¹ and R¹² substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R¹⁵ and R¹⁶ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R¹⁹ and R²⁰substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl. The symbol n is an integer from 0 to 5. Thesymbols m1, m2, m3, m4, v1, v2, v3, and v4 are independently 1 or 2. Thesymbols n1, n2, n3, and n4 are independently an integer from 0 to 4. Thesymbols X, X^(a), X^(b), X^(c) and X^(d) are independently —Cl, —Br, —I,or —F.

Embodiment 2

The compound of Embodiment 1, having the formula:

R⁵ is independently a hydrogen,halogen, —CX^(e) ₃, —CN, —SO₂Cl, —SO_(n5)R²⁶, —SO_(v5)NR²³R²⁴, —NHNH₂,—ONR²³R²⁴, —NHC═(O)NHNH₂, —NHC═(O)NR²³R²⁴, —N(O)_(m5), —NR²³R²⁴,—C(O)R²⁵,

—C(O)—OR²⁵, —C(O)NR²³R²⁴, —OR²⁶, —NR²³SO₂R²⁶, —NR²³C═(O)R²⁵,—NR²³C(O)—OR²⁵, —NR²³OR²⁵, —OCX^(e) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R²³, R²⁴, R²⁵, and R²⁶ are independently hydrogen,

halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R²³ and R²⁴ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. The symbols m5 and v5 are independently 1 or 2. The symboln5 is independently an integer from 0 to 4. The symbol X^(e) isindependently —Cl, —Br, —I, or —F.

Embodiment 3

The compound of Embodiment 2, wherein R⁵ is independently a hydrogen,halogen, —CX^(e) ₃, or unsubstituted alkyl.

Embodiment 4

The compound of Embodiment 2, wherein R⁵ is independently a hydrogen,—F, —CF₃, or unsubstituted methyl.

Embodiment 5

The compound of Embodiment 1, having the formula:

Embodiment 6

The compound of Embodiment 1, having the formula:

Embodiment 7

The compound of Embodiment 1, having the formula:

R⁵ is independently a hydrogen,halogen, —CX^(e) ₃, —CN, —SO₂Cl, —SO_(n5)R²⁶, —SO_(v5)NR²³R²⁴, —NHNH₂,—ONR²³R²⁴, —NHC═(O)NHNH₂, —NHC═(O)NR²³R²⁴, —N(O)_(m5), —NR²³R²⁴,—C(O)R²⁵,

—C(O)—OR²⁵, —C(O)NR²³R²⁴, —OR²⁶, —NR²³SO₂R²⁶, —NR²³C═(O)R²⁵,—NR²³C(O)—OR²⁵, —NR²³OR²⁵, —OCX^(e) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. R²³, R²⁴, R²⁵, and R²⁶ are independently hydrogen,

halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R²³ and R²⁴ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. The symbols m5 and v5 are independently 1 or 2. The symboln5 is independently an integer from 0 to 4, and the symbol X^(e) isindependently —Cl, —Br, —I, or —F.

Embodiment 8

The compound of Embodiment 7, wherein R⁵ is independently a hydrogen,halogen, —CX^(e) ₃, or unsubstituted alkyl.

Embodiment 9

The compound of Embodiment 7, wherein R⁵ is independently a hydrogen,—F, —CF₃, or unsubstituted methyl.

Embodiment 10

The compound of Embodiment 1, having the formula:

Embodiment 11

The compound of one of Embodiments 1 to 10, wherein L is a bond.

Embodiment 12

The compound of one of Embodiments 1 to 10, wherein L is aheteroalkylene.

Embodiment 13

The compound of one of Embodiments 1 to 10, wherein L is independently a2 to 8 membered heteroalkylene.

Embodiment 14

The compound of one of Embodiments 1 to 10, wherein L is independently a3 to 6 membered heteroalkylene.

Embodiment 15

The compound of one of Embodiments 1 to 10, wherein L is independently—NH-(substituted or unsubstituted (C₁-C₄) alkylene).

Embodiment 16

The compound of one of Embodiments 1 to 10, wherein L is independently—NH-(unsubstituted (C₁-C₄) alkylene).

Embodiment 17

The compound of one of Embodiments 1 to 10, wherein L is independently—NHC(O)-(substituted or unsubstituted (C₁-C₄) alkylene).

Embodiment 18

The compound of one of Embodiments 1 to 10, wherein L is independently—NHC(O)-(unsubstituted (C₁-C₄) alkylene).

Embodiment 19

The compound of one of Embodiments 1 to 18, wherein R² is independentlysubstituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl.

Embodiment 20

The compound of one of Embodiments 1 to 18, wherein R² is independentlysubstituted or unsubstituted (C₁-C₁₀) alkyl or substituted orunsubstituted 2 to 10 membered heteroalkyl.

Embodiment 21

The compound of one of Embodiments 1 to 18, wherein R² is unsubstitutedmethyl.

Embodiment 22

The compound of one of Embodiments 1 to 18, wherein R² is H.

Embodiment 23

The compound of one of Embodiments 1 to 22, wherein R³ is independentlysubstituted or unsubstituted alkyl or substituted or unsubstitutedheteroalkyl.

Embodiment 24

The compound of one of Embodiments 1 to 22, wherein R³ is independentlysubstituted or unsubstituted (C₁-C₁₀) alkyl or substituted orunsubstituted 2 to 10 membered heteroalkyl.

Embodiment 25

The compound of one of Embodiments 1 to 22, wherein R³ is unsubstitutedmethyl.

Embodiment 26

The compound of one of Embodiments 1 to 22, wherein R³ is H.

Embodiment 27

The compound of one of Embodiments 1 to 26, wherein R² and R³ are joinedto form a substituted or unsubstituted heterocycloalkyl.

Embodiment 28

The compound of one of Embodiments 1 to 26, wherein R² and R³ are joinedto form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

Embodiment 29

The compound of one of Embodiments 1 to 26, wherein R² and R³ are joinedto form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

Embodiment 30

The compound of one of Embodiments 1 to 26, wherein R² and R³ are joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl.

Embodiment 31

The compound of one of Embodiments 1 to 26, wherein R² and R³ and thenitrogen to which they are bonded form

Embodiment 32

The compound of one of Embodiments 1 to 31, wherein n is 2.

Embodiment 33

The compound of one of Embodiments 1 to 31, wherein n is 1.

Embodiment 34

The compound of one of Embodiments 1 to 5, wherein R¹ is —NO₂ or —NH₂.

Embodiment 35

The compound of Embodiment 34, wherein L is a bond.

Embodiment 36

The compound of Embodiment 1, having the formula:

Embodiment 37

A pharmaceutical composition comprising a compound of one of Embodiments1 to 36 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

Embodiment 38

A method of treating a hyperproliferative disorder in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of one of Embodiments 1 to 36, or a pharmaceuticallyacceptable salt thereof.

Embodiment 39

The method of Embodiment 39, wherein the hyperproliferative disorder isassociated with estrogen receptor activity.

Embodiment 40

The method of one of Embodiments 38 to 39, wherein thehyperproliferative disorder is lymphangioleiomyomatosis.

Embodiment 41

The method of one of Embodiments 38 to 39, wherein thehyperproliferative disorder is a cancer.

Embodiment 42

The method of Embodiment 41, wherein the cancer is resistant to ananti-cancer agent.

Embodiment 43

The method of one of Embodiments 41 to 42, wherein the cancer is breastcancer, lung cancer (e.g., non-small cell lung cancer), a gynecologicalcancer, ovarian cancer, endometrial cancer, or prostate cancer.

Embodiment 44

The method of one of Embodiments 41 to 42, wherein the cancer is acancer of an estrogen target organ or tissue.

Embodiment 45

A method of inhibiting estrogen receptor activity in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of one of Embodiments 1 to 36, or a pharmaceuticallyacceptable salt thereof.

Embodiment 46

A method of treating gynecomastia in a subject in need thereof,comprising administering to the subject an effective amount of acompound of one of Embodiments 1 to 36, or a pharmaceutically acceptablesalt thereof.

Embodiment 47

A method of treating a bone disorder in a subject in need thereof,comprising administering to the subject an effective amount of acompound of one of Embodiments 1 to 36, or a pharmaceutically acceptablesalt thereof.

What is claimed is:
 1. A compound having the formula:

wherein R¹ is independently a hydrogen, halogen, —NR²R³, —CX^(a) ₃, —CN,—SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR²R³, —NHNR²R³, —ONR²R³, —NHC═(O)NHNR²R³,—NHC═(O)NR²R³, —N(O)_(m1), —C(O)R⁹, —C(O)—OR⁹, —C(O)NR²R³, —OR¹⁰,—NR²SO₂R, —NR²C═(O)R⁹, —NR²C(O)—OR⁹, —NR²OR⁹, —OCX^(a) ₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; L is independently a bond, —NR⁴—, —NR⁴C(O)—,—C(O)NR⁴—, —O—, —S—, —C(O)—, —S(O)—, —S(O)₂—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene; or a substituted or unsubstitutedspirocyclic linker; R² is independently a hydrogen, halogen, —CX^(b) ₃,—CN, —SO₂Cl, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹²,—NHC═(O)NHNH₂, —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹², —C(O)R¹³,—C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX^(b) ₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R³ is independently a hydrogen, halogen, —CX^(c) ₃, —CN,—SO₂Cl, —SO₃R¹, —SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁵R¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷,—C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷,—NR¹⁵OR¹⁷, —OCX^(c) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² andR³ substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl; R⁴ is independently a hydrogen, halogen, —CX^(d) ₃, —CN,—SO₂Cl, —SO_(n4)R²², —SO_(v4)NR¹⁹R²⁰, —NHNH₂, —ONR¹⁹R²⁰, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁹R²⁰, —N(O)_(m4), —NR¹⁹R²⁰, —C(O)R²¹, —C(O)—OR²¹,—C(O)NR¹⁹R²⁰, —OR²², —NR¹⁹SO₂R²², —NR¹⁹C═(O)R²¹, —NR¹⁹C(O)—OR²¹,—NR¹⁹OR²¹, —OCX^(d) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, and R²² areindependently hydrogen, halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX₃, —OCHX₂,—CF₃, —OCF₃, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹ andR¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹⁵ and R¹⁶ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R¹⁹ and R²⁰ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; n is aninteger from 0 to 5; m1, m2, m3, m4, v1, v2, v3, and v4 areindependently 1 or 2; n1, n2, n3, and n4 are independently an integerfrom 0 to 4; X, X^(a), X^(b), X^(c) and X^(d) are independently —Cl,—Br, —I, or —F.
 2. The compound of claim 1, having the formula:

wherein R⁵ is independently a hydrogen, halogen, —CX^(e) ₃, —CN, —SO₂Cl,—SO_(n5)R²⁶, —SO_(v5)NR²³R²⁴, —NHNH₂, —ONR²³R²⁴, —NHC═(O)NHNH₂,—NHC═(O)NR²³R²⁴, —N(O)_(m5), —NR²³R²⁴, —C(O)R²⁵, —C(O)—OR²⁵,—C(O)NR²³R²⁴, —OR²⁶, —NR²³SO₂R²⁶, —NR²³C═(O)R²⁵, —NR²³C(O)—OR²⁵,—NR²³OR²⁵, —OCX^(e) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R²³,R²⁴, R²⁵, and R²⁶ are independently hydrogen, halogen, —CX₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²³and R²⁴ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; m5 and v5 are independently 1or 2; n5 is independently an integer from 0 to 4; X^(e) is independently—Cl, —Br, —I, or —F.
 3. The compound of claim 2, wherein R⁵ isindependently a hydrogen, halogen, —CX^(e) ₃, or unsubstituted alkyl. 4.The compound of claim 2, wherein R⁵ is independently a hydrogen, —F,—CF₃, or unsubstituted methyl.
 5. The compound of claim 1, having theformula:


6. The compound of claim 1, having the formula:


7. The compound of claim 1, having the formula:

wherein R⁵ is independently a hydrogen, halogen, —CX^(e) ₃, —CN, —SO₂Cl,—SO_(n5)R²⁶, —SO_(v5)NR²³R²⁴, —NHNH₂, —ONR²³R²⁴, —NHC═(O)NHNH₂,—NHC═(O)NR²³R²⁴, —N(O)_(m5), —NR²³R²⁴, —C(O)R²⁵, —C(O)—OR²⁵,—C(O)NR²³R²⁴, —OR²⁶, —NR²³SO₂R²⁶, —NR²³C═(O)R²⁵, —NR²³C(O)—OR²⁵,—NR²³OR²⁵, —OCX^(e) ₃, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R²³,R²⁴, R²⁵, and R²⁶ are independently hydrogen, halogen, —CX₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX₃, —OCHX₂, —CF₃, —OCF₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²³and R²⁴ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; m5 and v5 are independently 1or 2; n5 is independently an integer from 0 to 4; X^(e) is independently—Cl, —Br, —I, or —F.
 8. The compound of claim 7, wherein R⁵ isindependently a hydrogen, halogen, —CX^(e) ₃, or unsubstituted alkyl. 9.The compound of claim 7, wherein R⁵ is independently a hydrogen, —F,—CF₃, or unsubstituted methyl.
 10. The compound of claim 1, having theformula:


11. The compound of claim 1, wherein L is a bond.
 12. The compound ofclaim 1, wherein L is a heteroalkylene.
 13. The compound of claim 1,wherein L is independently a 2 to 8 membered heteroalkylene.
 14. Thecompound of claim 1, wherein L is independently a 3 to 6 memberedheteroalkylene.
 15. The compound of claim 1, wherein L is independently—NH-(substituted or unsubstituted (C₁-C₄) alkylene).
 16. The compound ofclaim 1, wherein L is independently —NH-(unsubstituted (C₁-C₄)alkylene).
 17. The compound of claim 1, wherein L is independently—NHC(O)-(substituted or unsubstituted (C₁-C₄) alkylene).
 18. Thecompound of claim 1, wherein L is independently —NHC(O)-(unsubstituted(C₁-C₄) alkylene).
 19. The compound of claim 1, wherein R² isindependently substituted or unsubstituted alkyl or substituted orunsubstituted heteroalkyl.
 20. The compound of claim 1, wherein R² isindependently substituted or unsubstituted (C₁-C₁₀) alkyl or substitutedor unsubstituted 2 to 10 membered heteroalkyl.
 21. The compound of claim1, wherein R² is unsubstituted methyl.
 22. The compound of claim 1,wherein R² is H.
 23. The compound of one of claim 1, wherein R³ isindependently substituted or unsubstituted alkyl or substituted orunsubstituted heteroalkyl.
 24. The compound of claim 1, wherein R³ isindependently substituted or unsubstituted (C₁-C₁₀) alkyl or substitutedor unsubstituted 2 to 10 membered heteroalkyl.
 25. The compound of claim1, wherein R³ is unsubstituted methyl.
 26. The compound of claim 1,wherein R³ is H.
 27. The compound of claim 1, wherein R² and R³ arejoined to form a substituted or unsubstituted heterocycloalkyl.
 28. Thecompound of claim 1, wherein R² and R³ are joined to form a substitutedor unsubstituted 3 to 8 membered heterocycloalkyl.
 29. The compound ofclaim 1, wherein R² and R³ are joined to form a substituted orunsubstituted 3 to 6 membered heterocycloalkyl.
 30. The compound ofclaim 1, wherein R² and R³ are joined to form an unsubstituted 3 to 6membered heterocycloalkyl.
 31. The compound of claim 1, wherein R² andR³ and the nitrogen to which they are bonded form


32. The compound of claim 1, wherein n is
 2. 33. The compound of claim1, wherein n is
 1. 34. The compound of claim 1, wherein R¹ is —NO₂ or—NH₂.
 35. The compound of claim 34, wherein L is a bond.
 36. Thecompound of claim 1, having the formula:


37. A pharmaceutical composition comprising a compound of one of claims1 to 36 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 38. A method of treating ahyperproliferative disorder in a subject in need thereof, comprisingadministering to said subject an effective amount of a compound of oneof claims 1 to 36, or a pharmaceutically acceptable salt thereof. 39.The method of claim 38, wherein said hyperproliferative disorder isassociated with estrogen receptor activity.
 40. The method of claim 38,wherein said hyperproliferative disorder is lymphangioleiomyomatosis.41. The method of claim 38, wherein said hyperproliferative disorder isa cancer.
 42. The method of claim 41, wherein said cancer is resistantto an anti-cancer agent.
 43. The method of claim 41, wherein said canceris breast cancer, lung cancer, a gynecological cancer, ovarian cancer,endometrial cancer, or prostate cancer.
 44. The method of claim 41,wherein said cancer is a cancer of an estrogen target organ or tissue.45. A method of inhibiting estrogen receptor activity in a subject inneed thereof, comprising administering to said subject an effectiveamount of a compound of one of claims 1 to 36, or a pharmaceuticallyacceptable salt thereof.